Open Access

Mouse models of atherosclerosis: a historical perspective and recent advances

  • Yee Ting Lee1,
  • Hiu Yu Lin1,
  • Yin Wah Fiona Chan2,
  • Ka Hou Christien Li3,
  • Olivia Tsz Ling To4,
  • Bryan P Yan4, 5,
  • Tong Liu6,
  • Guangping Li6,
  • Wing Tak Wong7,
  • Wendy Keung8 and
  • Gary Tse4, 9Email authorView ORCID ID profile
Lipids in Health and Disease201716:12

https://doi.org/10.1186/s12944-016-0402-5

Received: 28 October 2016

Accepted: 27 December 2016

Published: 17 January 2017

Abstract

Atherosclerosis represents a significant cause of morbidity and mortality in both the developed and developing countries. Animal models of atherosclerosis have served as valuable tools for providing insights on its aetiology, pathophysiology and complications. They can be used for invasive interrogation of physiological function and provide a platform for testing the efficacy and safety of different pharmacological therapies. Compared to studies using human subjects, animal models have the advantages of being easier to manage, with controllable diet and environmental risk factors. Moreover, pathophysiological changes can be induced either genetically or pharmacologically to study the harmful effects of these interventions. There is no single ideal animal model, as different systems are suitable for different research objectives. A good understanding of the similarities and differences to humans enables effective extrapolation of data for translational application. In this article, we will examine the different mouse models for the study and elucidation of the pathophysiological mechanisms underlying atherosclerosis. We also review recent advances in the field, such as the role of oxidative stress in promoting endoplasmic reticulum stress, mitochondrial dysfunction and mitochondrial DNA damage, which can result in vascular inflammation and atherosclerosis. Finally, novel therapeutic approaches to reduce vascular damage caused by chronic inflammation using microRNA and nano-medicine technology, are discussed.

Keywords

Mouse models Atherosclerosis ApoE LDL receptor Reactive oxygen species ER stress Mitochondrial dysfunction

Background

Atherosclerosis is responsible for acute myocardial infarction and cerebrovascular accidents, accounting for the majority of cardiovascular deaths. It is a chronic inflammatory disease characterized by the development of complex atherosclerotic plaques, leading to hardening and narrowing of the arterial lumen. Atherosclerotic plaque formation is initiated and sustained by a combination of endothelium dysfunction and chronic exposure to cardiovascular risk factors that promote vascular inflammation, such as hyperlipidemia, hypertension, smoking, male gender and diabetes.

Among these, the single most important risk factor is high plasma low density lipoprotein (LDL) level, of which a monogenetic cause is familial hypercholesterolemia [1]. Other risk factors are important in individuals with normal LDL levels. In the presence of a LDL level permissive of atherosclerotic plaque formation, these risk factors are important in explaining the development and progression of atherosclerotic lesions [2, 3]. Conversely, these are less important in individuals with very low LDL levels, who are unlikely to develop atherosclerosis irrespective of other risk factors [4]. With this in mind, cholesterol loading in the lesion-containing foam cells has been the focal point of intense research and has been studied extensively using different animal models. The extent of cholesterol loading is the result of lipoprotein uptake and lipid efflux in foam cells has been targeted therapeutically to reduce lesion size [5].

LDL accumulation

Excess LDL in plasma accumulate in the sub-endothelial space of arterial wall and undergoes oxidation to become oxidized LDL (oxLDL) [6]. This then triggers an inflammatory response and induces the expression of chemotactic protein such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin in the endothelium [7, 8]. The expression of adhesion molecules attracts blood cells into the injured arterial wall, with monocytes being the most prominent cell type [9]. Upon migration into the intimal layer, monocytes differentiate into macrophages which avidly internalize oxLDL and become foam cells themselves [10].

Foam cells present antigens to immune cells, such as circulating monocytes and T-cells, whose activation contributes critically to plaque development [11]. They also secrete mediators to perpetuate the inflammatory process in the arterial wall and to stimulate migration of smooth muscle cells from the tunica media into sub-endothelial space. Mediated by platelet derived growth factor, smooth muscle cells exhibit abnormally high proliferation rates and secrete extracellular matrix proteins that contribute to fibrous cap formation [12, 13]. The fibrous cap protects the core of the plaque from circulating blood cells, especially platelets that are responsible for the thrombosis associated with plaque rupture. This maladaptive response of a non-resolving inflammation is the driving force of atherosclerotic plaque development. It is worth noting that the SMCs from different regions of the microvasculature have different developmental origins [14], which can contribute to site-specific atherosclerosis responses [15].

During plaque evolution, macrophages proliferate and undergo apoptosis and efferocytosis [16, 17]. Depending on the efficiency of efferocytosis, apoptotic cells may be removed, leading to reduction of lesion size [18], or they may accumulate and be subjected to secondary necrosis, producing a necrotic core characteristic of advanced plaques. The accumulation of apoptotic bodies will enhance the plaque instability by triggering inflammation [19, 20].

Whilst foam cells are the most abundant leukocytes within the atherosclerotic lesion, studies in mouse models have implicated other cell types, including neutrophils, T-and B-cell, and mast cells, in atherogenesis [21, 22]. These cells, though contribute little to the lesion mass, can influence atherosclerosis by secreting variety of proteins that regulate other cells or components within the plaque. Experiment studies using mice have demonstrated that among the subsets of T-cells, Th1 cells and natural killer T-cells are notably pro-atherogenic, whilst the role of Th2 and Th17 cells are less well understood [2325].

Plaque rupture

Plaque rupture is responsible for the adverse consequences of ischemic events in acute myocardial infarction and cerebrovascular accidents and death [26]. At advanced stages of atherosclerosis, rupture of vulnerable plaques exposes their thrombogenic compounds, thereby leading to luminal thrombosis [27]. Macrophage-derived proteases, especially metalloproteases, can destabilize plaques, but the exact underlying mechanism of plaque vulnerability remained incompletely elucidated [28].

Animal models of atherosclerosis

The first key piece of evidence that atherosclerosis is inducible in laboratory animals was provided by Ignatowski in 1908, who demonstrated lesion formation in the aortic wall of rabbits that were fed a diet enriched in animal protein (mainly meat, milk, and egg yolk). Since then, various animal species, such as rabbits, mice, rats, guinea pigs, hamsters, birds, dogs and non-human primates, have been used for experimentation. Of these, rodents, swine and rabbits have provided crucial information for the pathophysiological mechanisms underlying the initiation and subsequent development of atherosclerotic plaques. In spite of the many differences between the animal models, all of these demonstrate the requirement of high blood cholesterol levels for plaque development. The observations of this remarkable characteristic supported the discovery of the essential role of cholesterol in atherosclerosis development. Animal models have been extensively used for the study of human cardiovascular diseases [2940], and their use has led to opportunities for translational application [32, 4145]. In this review, the different models for examining atherosclerosis, their own advantages and disadvantages (Table 1) and the molecular pathways involved (Table 2), will be discussed in turn.
Table 1

Advantages and disadvantages of mouse models for studying atherosclerosis

Advantages

Disadvantages

Ease of genetic manipulation

Toxic diet needed to induce atherosclerosis in wild-type mice

Low maintenance cost

Different lipid metabolism compared to humans: high HDL, no CETP

Short generation time means less time consuming for research projects

Differing cardiovascular anatomy and physiology with different predisposed site for the development atherosclerosis

Wide availability

Small body size limits frequent blood collection and increases difficulty of dissection of small arteries

Table 2

Molecular pathways involved in atherosclerosis

Molecular mechanisms

Role in Atherosclerosis

References

Expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin

Inflammatory response induced by LDL oxidation

[7, 8]

Nuclear factor-kappa B (NF-κB) activation

Chemotaxis via regulation of chemokines, such as CCL2, CCL5, CCL8, and CXCL9

[166, 169]

Release of platelet derived growth factor

Fibrous cap formation

[12, 13]

CHOP activation

Macrophage apoptosis via endoplasmic reticulum stress

[107, 108]

Pattern recognition receptor activation

Macrophage apoptosis via activation of CD36-TLR2 pathway

[111, 112]

Activation of mitochondrial, Ca2+-dependent pathways

Vascular smooth muscle cell apoptosis via calpain/mPTP/cytochrome C/caspase-3 and apoptosis-inducing factor

[140]

cytochrome c release and activation of caspase-9 and the effector caspases

Macrophage apoptosis induced by cholesterol loading

[141]

Toll-like receptor activation

Immune activation through recognition of mitochondrial DNA, which can act as damage-associated molecular patterns (DAMPs)

[148]

Upregulation of transient receptor potential cation (TRPC) channels

VSMC, migration, proliferation and apoptosis; neointimal proliferation

[158, 160162]

Mouse

With its small size and ease of genetic manipulation, the mouse is currently the most frequently used model in atherosclerosis research [46]. Development of atherosclerosis is influenced by a number of genes, which interact with each other and the environment to affect the disease phenotype [47]. Manipulation can take place for single genes, and indeed in a time-dependent manner, which permits the elucidation of the molecular mechanisms operating in different phase of plaque evolution, whilst the manipulation of gene expression in specific cell types has increased our understanding of the contributions of different immune cells to atherosclerosis.

Dietary models

The first mouse model was developed by Wissler and coworkers in 1960s [48]. They fed the mice with a diet of high fat 30%, high cholesterol 5% and cholic acid 2%. This diet successfully promoted hypercholesterolemia, and induced the formation of fatty streaks in different vascular regions [49]. However, the high fat diet induced a high level of acute inflammatory changes, but did not simulate the chronic low-grade inflammatory environment observed in human atherosclerosis [50]. Also, the pro-inflammatory diet as highly toxic, which led to weight loss and increased the susceptibility of the animals to infections.

A less toxic diet of 15% fat, 1.25% cholesterol and 0.5% cholic acid was introduced, resulting in high variability of diet-induced atherosclerosis in different strains of mice [51]. The most susceptible strain was C57BL/6, which developed mild hypercholesterolemia — around 200 mg/ml — and fatty streak lesions in the aortic root after 3–9 months of fat feeding [52]. However, the lesion was not comparable to that observed in humans, with small lesions found in the aorta, consisted almost exclusively of macrophages and did not progress to fibrous plaques. The difference in morphology of the plaque formation between mouse and human hampers data extrapolation. Nevertheless, from experiments conducted in dietary models, a number of genetic loci that increase the susceptibility to atherosclerosis has been identified. An example is Ath-1, which was mapped to the short arm of chromosome 1 [53].

Recent experiments in germ-free mice generated by feeding with an antibiotic cocktail have demonstrated dietary lipid phosphatidylcholine (lecithin) was identified by a metabolomics approach, and these were subsequently shown to be predictive of atherosclerosis in humans, highlighting the role of intestinal microbiome in regulating plasma lipoprotein homeostasis [54].

ApoE knockout and LDLR-deficient models

Given the toxicity of high fat diet and differences in lesion morphology, limitations of using wild-type mice for studying atherosclerosis were recognized. The development of genetically modified mice represented a breakthrough. Gene knockout and knock-in techniques, together with the ability to control the spatial and temporal patterns of gene expression, have proven useful for studying atherosclerosis. The first genetically modified mouse model developed was the Apolipoprotein E (ApoE) knockout model [55]. ApoE is a structural component of all lipoprotein except for LDL and is a critical ligand for the hepatic clearance of plasma lipoproteins mediated by LDLR and LDLR-related protein [5658]. ApoE knockout mice exhibited significant hypercholesterolemia (400 mg/dl, which represents a five-fold increase in plasma cholesterol level compared to wild type mice) despite being on a low fat diet [5961]. An advantage of using ApoE knockout mice is that the high toxic diet can be avoided. Moreover, it shares greater degrees of similarity in the atherosclerotic development to humans compared to wild-type models. There is dramatic shift in plasma lipoprotein profile, with the proatherogenic VLDL as the most abundant circulating lipoprotein, similar to type II hyperlipidemia in humans [62]. Spontaneous development of atherosclerotic lesions in several vascular beds, predominantly in the aortic root, aortic arch and different branch point along the aorta, are observed [63]. Another advantage is the rapid development of lesions compared to wild-type. When ApoE knockout mice are fed with a high fat diet [64, 65] (Western type diet, which contains 0.15% cholesterol, 21% fat derived from milk and without the use of cholic acid), they exhibit high plasma lipid level of over 1000 mg/dl and develop complex fibrous plaques in the aortic sinus after 10–14 weeks of diet.

However, ApoE knockout mice has its own drawbacks which limits the extrapolation of data derived from this model to humans. Firstly, the lipid metabolism is dissimilar, with the majority of the plasma cholesterol as VLDL but not LDL as observed in humans [66, 67]. Secondly, ApoE was found to provide extra athero-protective properties in addition to mediating lipoprotein clearance, by virtue of its anti-oxidative, anti-proliferative and anti-inflammatory actions [68]. Therefore, atherosclerosis in ApoE knockout model may be independent of plasma lipid levels. Conversely, low levels of ApoE expressed in adrenal cells can reduce the severity of atherosclerosis without affecting plasma lipid levels in ApoE-deficient mice [69].

To overcome the problems of the above model, LDLR deficient mouse model was developed. Compared to ApoE, LDLR has fewer functions and therefore the effects due to its absence are more easily attributed to lipoprotein homeostasis than other processes such as cell proliferation or inflammation [70]. LDLR deficiency impairs lipoprotein uptake and clearance, resulting in a greater preponderance of LDL as the cholesterol-carrying plasma lipoprotein. Compared to ApoE knockout mice, this model shows a milder plasma cholesterol increase of 250 mg/dl when fed with standard low fat diet and the elevated lipoprotein is mainly LDL [71]. Whilst on high fat diet, LDLR-deficient animals developed severe hypercholesterolemia of 900 mg/dl with accumulation of VLDL and LDL, as well as extensive atherosclerosis [72].

Compared with ApoE deficiency, the absence of functional LDLR in humans is more common and leads to familial hypercholesterolemia, greatly increasing the cardiovascular risk [73]. This model shares the characteristics observed in human familial hypercholesterolemia, including the lesions in aortic valves and the aortic root [74]. This model has been useful for examining the relationship between diabetes and atherosclerosis, which often co-exist [72]. It was found that LDLR deficient mice were more prone to obesity and insulin resistance than ApoE deficient mice.

However, the LDLR model is imperfect with its own shortcoming. Firstly, compared with the ApoE knockout mice, the LDLR deficient mouse model is more resistant to injury-induced neointimal formation [75]. Therefore, ApoE knockout mice remains the better alternative for investigating the molecular mechanisms underlying restenosis following angioplasty [76]. Secondly, limited lesions developed only in older LDLR deficient mice with standard diet [77, 78]. Consequently, high fat diets with different levels of cholesterol have been employed to induce more significant atherosclerotic changes [79]. With a variety of dietary cholesterol intake, this model cannot be standardized across models generated by different laboratories.

Advantages and disadvantages of mouse models

The advantages of using small sized animals over larger animals are lower costs to purchase, breed, feed and maintain. The use of antibodies and drugs for intervention becomes more affordable with its small size. Another advantage is its rapid growth rate and short generation time [80]: it takes 6 to 8 weeks for the mouse to reach sexual maturity and approximately an additional 3 weeks for gestation [81]. It is relatively easy to control multiple genes by interbreeding given the wide availability of inbred strains [82], or using genetic knockout techniques to elucidate the role of individual genes in atherosclerosis [83]. The ease of genetic manipulation comes in the well-defined genetic makeup and availability of inbred strains.

The major limitation of mouse models is their natural resistance to atherosclerosis for several reasons. Firstly, cholesterol metabolism and lipoprotein pattern are different from those of humans due to the absence of cholesteryl ester transfer protein (CETP) [84], a carrier that facilitates the transport of cholesteryl esters and triglycerides between different lipoproteins [85]. Thus, mice usually have a lower plasma cholesterol levels of 60–100 mg/dl compared to humans, with the high density lipoprotein being the major circulating lipoprotein [86]. This contrasts with the deleterious LDL, which is the predominant form found in plasma of humans [87]. Thus, genetically-modified mice have been used to induce hypercholesterolemia, although concerns have been raised because this may be non-physiological and the pathogenesis may differ from that of human atherosclerosis [88].

Although the comparatively smaller size of mice results in more convenient use for experimentation, it also limits many aspects of practical investigation. For example, the coronary arteries are too small for visualization. Moreover, blood collection can be difficult [89]. There is also considerable difference in the anatomy of the cardiovascular system between mice and humans. The arterial intima consists of only endothelium overlying the internal elastic lamina without smooth muscle cells or connective tissues found in humans [90]. Moreover, the tunica media is less thick and the vasa vasorum is absent in mice [91].

The morphology of atherosclerotic lesions observed in mice is different from that of humans, in that the thick fibrous cap is absent [92]. In mice, vasa vasorum is not needed since the thin layers of tunica intima and intima do not pose a significant barrier to oxygen diffusion [91]. The absence of the vasa vasorum explains the lack of ingrowth of neovessels into the base of the lesions. The neovessel is thought to be derived from the vasa vasorum, considered as an important entry path for immune cells and contributes to chronic inflammation and development of the necrotic core [93]. The predilection sites for atherosclerosis development in mouse models are the aortic sinus and innominate artery, whereas the coronary arteries are commonly affected in humans. Unstable plaque is rarely observed in mouse models, and it is therefore difficult to examine plaque rupture and overlying luminal thrombosis, which is the direct cause of acute ischemic events responsible for cardiovascular deaths, using these systems [9496].

Recent advances

Oxidative stress, dysfunction of intracellular organelles and vascular inflammation

Recent research efforts have focused on elucidating the mechanisms by which dysfunction of two intracellular organelles, the endoplasmic reticulum (ER) and the mitochondrion of various cell types, promotes vascular inflammation and atherosclerosis.

ER stress

The ER is responsible for protein synthesis, proper folding, maturation and assembly prior to further processing by the Golgi apparatus [97]. The highly oxidative environment within the ER lumen facilitates the formation of tertiary and quaternary structures, aided by chaperone proteins and a high concentration of luminal Ca2+ to facilitate their interactions [98]. Abnormalities in these processes can lead to misfolding or unfolding of proteins, which then accumulate within the ER lumen. This would increase ER stress, thereby activating the unfolded protein response (UPR) [99]. The UPR is a normal adaptive and protective mechanism to reduce the rate of protein synthesis, increase folding ability of proteins and aid misfolded or unfolded protein to cellular degradation pathways [100].

Prolonged ER stress of different cell types involved in atherosclerosis, including macrophages, VSMCs and endothelial cells, has been observed in atherosclerosis [101103]. In macrophages, LDL and cholesterol are transported from late endosomes to the ER, where esterification of cholesterol and formation of lipid droplets occur [104]. In macrophages of atherosclerotic plaques, the esterification process is greatly reduced, which is responsible for cholesterol accumulation in foam cells [105]. It has been shown that UPR activation of macrophages takes place during the different stages of atherosclerotic lesion development in ApoE knockout mice [106]. Prolonged ER stress leads to macrophage apoptosis associated with expression of the UPR sensor C/EBPα-homologous protein (CHOP). CHOP inactivation could reduce the rate of macrophage apoptosis and plaque necrosis, suggesting that targeting of the UPR has the potential to hinder the progression of atherosclerosis [107, 108]. In early plaques, macrophages are efficient in clearing cells which have undergone apoptosis [109]. However, in advanced plaques, they are unable to do so [110], resulting in the formation of necrotic core [111]. Other mechanisms contributing to apoptosis of macrophages require activation of pattern recognition receptors (PRRs) of the innate immune system by oxidized lipids [111, 112]. PRR activation induces apoptosis via the CD36-TLR2 pathway [112]. In this pathway, the enzyme NADPH oxidase plays a key role in mediating oxidative stress, activation of the double-stranded RNA-dependent protein kinase, which induces CHOP and apoptosis [113].

ER stress in endothelial cells can be activated by shear stress [114, 115] or oxLDL [116]. This results in increased oxidative stress and therefore increased oxidation of sarcoplasmic/endoplasmic reticulum Ca2+-dependent ATPase, leading to atherogenesis [116]. In VSMCs, a number of cellular stressors, such as cholesterol loading, can initiate ER stress [117, 118], thereby activating apoptosis [119]. This may then affect collagen synthesis adversely. Homocysteine, which is raised in hypertension and diabetes, can initiate UPR [117]. ER stress plays a role in cardio-metabolic disorders such as hypertension and diabetes, and partly explains why atherosclerosis is worsened in the presence of these co-morbid conditions [120122]. The use of mouse models has discovered novel mechanisms by which traditional pharmacological agents act to exert their vascular protective effects through modifying ER stress response [122124]. For example, recent experiments have demonstrated that metformin, a commonly used anti-diabetic drug, protected endothelial function in obese, diabetic mice by inhibiting ER stress [120].

Mitochondrial dysfunction

The mitochondria are the cellular powerhouses because of their ability to generate ATP by oxidative phosphorylation. They have other functions such as, redox status, reactive oxygen species (ROS) production and regulation of cellular apoptosis [125]. They are the only intracellular organelle apart from the nucleus to contain DNA. During ATP synthesis, electron is transferred from complex I to complex IV of the respiratory chain, which leads to pumping of protons from the mitochondrial matrix into the intermembrane space [126]. Much of the cellular ROS is derived from the mitochondria, mostly from complex I and complex III and enzymes including the alpha-ketoglutarate dehydrogenase complex and those participating in fatty acid beta-oxidation [127130]. Production of oxygen free radicals is more efficient by reverse electron transfer dependent on succinate (through complex I to NAD+) than forward electron transfer with NADH [131]. This reverse electron transfer is an important mechanism of ROS production in many pathological conditions such as hypertension, playing an important role in the development of atherosclerosis [132]. Mitochondrial ROS can itself increase its own production in a positive feedback loop, which is termed ROS-induced ROS release (RIRR) [133, 134]. This is recognized to play a key role initiating mitochondrial depolarization [134].

Elevated ROS production can damage a number of macromolecules within the cells, such as proteins, lipids and mitochondrial DNA of different cell types, contributing to atherosclerosis development (Fig. 1). For example, 4-Hydroxynonenal (HNE), an end-product of membrane lipid peroxidation [135], increased ROS production, producing mitochondrial dysfunction and inducing VSMC apoptosis [136]. Reperfusion after ischaemia, which a consequence of atherosclerotic disease, can lead to opening of the mitochondrial permeability transition pore (MPTP) [137, 138]. MPTP opening transiently leads to depolarization of the mitochondrial membrane potential. However, prolonged opening is harmful, as it leads to swelling of the mitochondrial matrix, and rupture of the outer membrane, releasing pro-apoptotic factors to initiate apoptosis [139]. VSMC apoptosis induced by oxidize LDL occurs via two distinct mitochondrial, Ca2+-dependent pathways, calpain/mPTP/cytochrome C/caspase-3 and apoptosis-inducing factor [140]. Other cell types such as macrophages also demonstrate mitochondrial dysfunction. Thus, cholesterol loading in macrophages triggers cytochrome c release and activation of caspase-9 and the effector caspases, leading to macrophage apoptosis [141]. Moreover, oxLDL can increase the release of peroxyl radicals, inducing both mitochondrial depolarization, dysfunction and cell lysis in macrophages [142].
Fig. 1

The role of mitochondrial dysfunction in promoting atherosclerosis. OxLDL: oxidized LDL. MtDNA: mitochondrial DNA. ROS: reactive oxygen species. RIRR: ROS-induced ROS release. VSMC: vascular smooth muscle cell

There has been a recent interest in the consequences of mitochondrial DNA damage in atherosclerosis. The relationship between mitochondrial DNA damage and oxidative stress has been studied in detail using genetically knockout mice with expressing a proofreading-deficient version of the mitochondrial DNA Polymerase G (POLG) [143, 144]. Mitochondrial DNA damage occurs early in atherogenesis [145]. Mice with double knockout of ApoE and POLG accumulate mitochondrial DNA damage, which promoted atherosclerosis and was associated with the formation of vulnerable plaques [146]. In ApoE-deficient recipients of mutator-mouse bone marrow, fibrous cap thinning and increased necrotic core, which are characteristic of vulnerable plaques, were observed [147]. It is thought that mitochondrial DNA can act as damage-associated molecular patterns (DAMPs), which are recognized by Toll-like receptors (TLRs). TLRs can activate the innate immune system [148].

Current treatment options and complications

The mainstay treatment options for occlusive vascular disease are stent insertion or bypass grafting. However, significant complications such as stent thrombosis, re-stenosis or vein graft failure can arise [149151]. There is therefore a need to elucidate the molecular mechanisms underlying these harmful processes in order to devise ways to prevent them. In recent years, the role of oxidative stress, endoplasmic reticulum stress and mitochondrial dysfunction in promoting neointimal proliferation has been intensively studied [152]. VSMCs, the main component of the neointima, are capable of switching from a quiescent and contractile to a proliferative phenotype [153]. The latter is responsible for luminal occlusion. Increased ROS release causes neointimal hyperplasia by promoting VSMC migration and proliferation, as well as collagen deposition within the extracellular matrix [16, 154, 155]. Altered Ca2+ signalling plays a critical role in these processes [156, 157]. For example, L-type Ca2+ channels are downregulated and transient receptor potential cation (TRPC) channels are upregulated in VSMCs [156]. Of the TRPCs, the Ca2+-permeable TRPM2 channel was suggested to be a sensor of oxidative stress [158], and its activation by ROS leads to intracellular Ca2+ overload inflammation [159], VSMC, migration, proliferation and apoptosis [158, 160, 161]. Another TRPC isoform, TRPC1, has also been implicated in neointimal proliferation [162].

Future therapeutic approaches: microRNAs and nanoparticle delivery

The roles of microRNAs in atherosclerosis have been the focus of research in recent years [163]. The use of this model has led to novel therapeutic approaches. MicroRNAs are non-coding RNAs involved in post-transcriptional regulation of genes by RNA silencing [164]. Their generation is under tight control spatially and temporally. Recent work has demonstrated their regulation of flow-dependent vascular remodelling [165]. It appears that some microRNAs, such as miR-10a, miR-19a, and miR-23b are inducible by shear stress and play a protective role in atherosclerosis [166168]. Other microRNAs, such as MiR-146a and miR-181b, have anti-inflammatory properties by inhibiting the translation of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and importin α3. This results in inhibition of nuclear factor-kappa B (NF-κB) activity, which is critical in regulating the expression of several chemokines, such as CCL2, CCL5, CCL8, and CXCL9 [166, 169]. In a recent study, polyethylene glycol-polyethyleneimine nanoparticles were used as vectors for microRNA delivery targeting E-selectin of inflamed endothelium of ApoE-deficient mice, which ameliorated endothelial inflammation and atherosclerosis [170]. Phosphatidylserine-based nanoparticles delivering the natural dietary compound curcumin was able to target macrophages and reduce their pro-inflammatory action [171]. Polyethylene glycol-conjugated polyion complex (PIC) vesicles containing drugs were injected into carotid arteries of rats using a balloon catheter, resulting in sustained targeted delivery, providing a proof-of-concept that this approach can be used for treating atherosclerosis in the future [172].

Conclusions

There is no single ideal animal model for studying a particular clinical condition [173175]. The general criteria for an appropriate animal model lies are the size, docility, ease of breeding and housing, known genetic profile, analogies with humans and the costs involved. Mice are amenable to genetic modification, allowing identification of genes contributing to the development of atherosclerosis. The understanding on the risk factors and natural history of atherosclerosis offer insights on disease prevention. Identification of the molecular events is important for developing therapeutic strategies to improve endothelial dysfunction, which could slow or even reverse disease progression in atherosclerosis [176, 177].

Abbreviations

ApoE: 

ApolipoproteinE

CETP: 

Cholesteryl ester transfer protein

CHOP: 

C/EBPα-homologous protein

DAMP: 

Damage-associated molecular patterns

ER: 

Endoplasmic reticulum

LDL: 

Lipoprotein

MPTP: 

Mitochondrial permeability transition pore

NF-κB: 

Nuclear factor-kappa B

oxLDL: 

Oxidized LDL

POLG: 

Polymerase G

PRR: 

Pattern recognition receptors

RIRR: 

ROS-induced ROS release

ROS: 

Reactive oxygen species

TLR: 

Toll-like receptor

TNF: 

Tumor necrosis factor

TRAF6: 

TNF-associated factor 6

TRPC: 

Transient receptor potential cation channel

VSMC: 

Vascular smooth muscle cell

Declarations

Acknowledgements

None.

Funding

YC is supported by a project grant from the ESRC for her doctoral studies at the University of Cambridge. GT was supported by the BBSRC Doctoral Training Award and Assistant Professorships from The Croucher Foundation of Hong Kong. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Authors’ contributions

YL Literature review; design of manuscript; drafted and critically revised the manuscript for important intellectual content; preparation of figure. HL Literature review; Drafted and critically revised the manuscript for important intellectual content. VL critically revised the manuscript for important intellectual content. YC critically revised the manuscript for important intellectual content. OT critically revised the manuscript for important intellectual content. BY critically revised the manuscript for important intellectual content. TL critically revised the manuscript for important intellectual content. WW critically revised the manuscript for important intellectual content. GT Literature review; drafted and critically revised the manuscript for important intellectual content; preparation of figure. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

N/A

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong
(2)
School of Biological Sciences, University of Cambridge
(3)
Faculty of Medicine, Newcastle University
(4)
Department of Medicine and Therapeutics, Chinese University of Hong Kong
(5)
Department of Epidemiology and Preventive Medicine, Monash University
(6)
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University
(7)
School of Life Sciences, Chinese University of Hong Kong
(8)
Stem Cell & Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam
(9)
Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong

References

  1. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society. Eur Heart J. 2013;34:3478–3490a.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2224–60.PubMedPubMed CentralView ArticleGoogle Scholar
  3. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–52.PubMedView ArticleGoogle Scholar
  4. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation. 2008;118:672–7.PubMedView ArticleGoogle Scholar
  5. Yvan-Charvet L, Wang N, Tall AR. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol. 2010;30:139–43.PubMedView ArticleGoogle Scholar
  6. Parthasarathy S, Quinn MT, Steinberg D. Is oxidized low density lipoprotein involved in the recruitment and retention of monocyte/macrophages in the artery wall during the initiation of atherosclerosis? Basic Life Sci. 1988;49:375–80.PubMedGoogle Scholar
  7. Braun M, Pietsch P, Felix SB, Baumann G. Modulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on human coronary smooth muscle cells by cytokines. J Mol Cell Cardiol. 1995;27:2571–9.PubMedView ArticleGoogle Scholar
  8. Li H, Cybulsky MI, Gimbrone Jr MA, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993;13:197–204.PubMedView ArticleGoogle Scholar
  9. Joris I, Stetz E, Majno G. Lymphocytes and monocytes in the aortic intima—an electron-microscopic study in the rat. Atherosclerosis. 1979;34:221–31.PubMedView ArticleGoogle Scholar
  10. Proudlock JW, Day AJ, Tume RK. Cholesterol-esterifying enzymes of foam cells isolated from atherosclerotic rabbit intima. Atherosclerosis. 1973;18:451–7.PubMedView ArticleGoogle Scholar
  11. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131–8.PubMedView ArticleGoogle Scholar
  12. Sano H, Sudo T, Yokode M, Murayama T, Kataoka H, Takakura N, Nishikawa S, Nishikawa SI, Kita T. Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice. Circulation. 2001;103:2955–60.PubMedView ArticleGoogle Scholar
  13. Kozaki K, Kaminski WE, Tang J, Hollenbach S, Lindahl P, Sullivan C, Yu JC, Abe K, Martin PJ, Ross R, et al. Blockade of platelet-derived growth factor or its receptors transiently delays but does not prevent fibrous cap formation in ApoE null mice. Am J Pathol. 2002;161:1395–407.PubMedPubMed CentralView ArticleGoogle Scholar
  14. Majesky MW. Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol. 2007;27:1248–58.PubMedView ArticleGoogle Scholar
  15. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 2004;24:12–22.PubMedView ArticleGoogle Scholar
  16. Ley K, Miller YI, Hedrick CC. Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol. 2011;31:1506–16.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–55.PubMedPubMed CentralView ArticleGoogle Scholar
  18. Van Vre EA, Ait-Oufella H, Tedgui A, Mallat Z. Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:887–93.PubMedView ArticleGoogle Scholar
  19. Kolodgie FD, Narula J, Haider N, Virmani R. Apoptosis in atherosclerosis. Does it contribute to plaque instability? Cardiol Clin. 2001;19:127–39. ix.PubMedView ArticleGoogle Scholar
  20. Martinet W, Kockx MM. Apoptosis in atherosclerosis: focus on oxidized lipids and inflammation. Curr Opin Lipidol. 2001;12:535–41.PubMedView ArticleGoogle Scholar
  21. Baetta R, Corsini A. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis. 2010;210:1–13.PubMedView ArticleGoogle Scholar
  22. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–15.PubMedView ArticleGoogle Scholar
  23. Lahoute C, Herbin O, Mallat Z, Tedgui A. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol. 2011;8:348–58.PubMedView ArticleGoogle Scholar
  24. Getz GS, Vanderlaan PA, Reardon CA. Natural killer T cells in lipoprotein metabolism and atherosclerosis. Thromb Haemost. 2011;106:814–9.PubMedPubMed CentralView ArticleGoogle Scholar
  25. Butcher M, Galkina E. Current views on the functions of interleukin-17A-producing cells in atherosclerosis. Thromb Haemost. 2011;106:787–95.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Chen YC, Huang AL, Kyaw TS, Bobik A, Peter K. Atherosclerotic plaque rupture: identifying the straw that breaks the Camel’s back. Arterioscler Thromb Vasc Biol. 2016;36:e63–72.PubMedView ArticleGoogle Scholar
  27. Kalz J, ten Cate H, Spronk HM. Thrombin generation and atherosclerosis. J Thromb Thrombolysis. 2014;37:45–55.PubMedView ArticleGoogle Scholar
  28. Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2008;28:2108–14.PubMedView ArticleGoogle Scholar
  29. Choy L, Yeo JM, Tse V, Chan SP, Tse G. Cardiac disease and arrhythmogenesis: mechanistic insights from mouse models. Int J Cardiol Heart Vasc. 2016;12:1–10.PubMedPubMed CentralGoogle Scholar
  30. Hu Z, Chen Z, Wang Y, Jiang J, Tse G, Xu W, Ge J, Sun B. Effects of granulocyte colony-stimulating factor on rabbit carotid and swine heart models of chronic obliterative arterial disease. Mol Med Rep. 2016.Google Scholar
  31. Tse G, Lai ET, Tse V, Yeo JM. Molecular and electrophysiological mechanisms underlying cardiac arrhythmogenesis in diabetes mellitus. J Diabetes Res. 2016;2016:2848759.PubMedPubMed CentralView ArticleGoogle Scholar
  32. Tse G. Both transmural dispersion of repolarization and of refractoriness are poor predictors of arrhythmogenicity: a role for iCEB (QT/QRS)? J Geriatr Cardiol. 2016;13(9):813–4.PubMedPubMed CentralGoogle Scholar
  33. Chen Z, Sun B, Tse G, Jiang J, Xu W. Reversibility of both sinus node dysfunction and reduced HCN4 mRNA expression level in an atrial tachycardia pacing model of tachycardia-bradycardia syndrome in rabbit hearts. Int J Clin Exp Pathol. 2016;9:8526–31.Google Scholar
  34. Chuang C-S, Ho S-C, Lin C-L, Lin M-C, Kao C-H. Risk of cerebrovascular events in pneumoconiosis patients: a population-based study, 1996–2011. Medicine. 2016;95:e2944.PubMedPubMed CentralView ArticleGoogle Scholar
  35. Lin HY, Lee YT, Chan YW, Tse G. Animal models for the study of primary and secondary hypertension in humans. Biom Rep. 2016;5:653–9.Google Scholar
  36. Yeo JM, Tse V, Kung J, Lin HY, Lee YT, Kwan J, Yan BP, Tse G. Isolated heart models for studying cardiac electrophysiology: a historical perspective and recent advances. J Basic Clin Physiol Pharmacol. 2016. in press.Google Scholar
  37. Fu H, Li G, Liu C, Li J, Cheng L, Yang W, Tse G, Zhao J, Liu T. Probucol prevents atrial ion channel remodeling in an alloxan-induced diabetes rabbit model. Oncotarget. 2016. ahead of print.Google Scholar
  38. Tse G, Yeo JM, Tse V, Kwan SK, Sun B. Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by decreasing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts. Mol Med Rep. 2016;14(5):4069–74.PubMedPubMed CentralGoogle Scholar
  39. Tse G, Liu T, Li KH, Laxton V, Chan YW, Keung W, Li RA, Yan BP. Electrophysiological mechanisms of Brugada syndrome: insights from pre-clinical and clinical studies. Front Physiol. 2016;7:467.PubMedPubMed CentralGoogle Scholar
  40. Tse G, Lai ETH, Yeo JM, Tse V, Wong SH. Mechanisms of electrical activation and conduction in the gastrointestinal system: lessons from cardiac electrophysiology. Front Physiol. 2016;7:182. doi:10.3389/fphys.2016.00182.
  41. Tse G. (Tpeak — Tend)/QRS and (Tpeak — Tend)/(QT x QRS): novel markers for predicting arrhythmic risk in the Brugada syndrome. Europace. 2016. ahead of print.Google Scholar
  42. Tse G, Yan BP. Traditional and novel electrocardiographic conduction and repolarization markers of sudden cardiac death. Europace. 2016. ahead of print.Google Scholar
  43. Tse G. Novel conduction-repolarization indices for the stratification of arrhythmic risk. J Geriatr Cardiol. 2016;9:811–2.Google Scholar
  44. Tse G, Wong ST, Tse V, Yeo JM. Variability in local action potential durations, dispersion of repolarization and wavelength restitution in aged wild-type and Scn5a+/− mouse hearts modelling human Brugada syndrome. J Geriatr Cardiol. 2016. in press.Google Scholar
  45. Tse G, Wong ST, Tse V, Yeo JM. Determination of action potential wavelength restitution in Scn5a+/− mouse hearts modelling human Brugada syndrome. J Geriatr Cardiol. 2016. in press.Google Scholar
  46. Mukhopadhyay R. Mouse models of atherosclerosis: explaining critical roles of lipid metabolism and inflammation. J Appl Genet. 2013;54:185–92.PubMedView ArticleGoogle Scholar
  47. Simmons RD, Kumar S, Jo H. The role of endothelial mechanosensitive genes in atherosclerosis and omics approaches. Arch Biochem Biophys. 2016;591:111–31.PubMedView ArticleGoogle Scholar
  48. Vesselinovitch D, Wissler RW, Doull J. Experimental production of atherosclerosis in mice. Atherosclerosis. 1968;8:483–95.View ArticleGoogle Scholar
  49. Thompson JS. Atheromata in an inbred strain of mice. J Atheroscler Res. 1969;10:113–22.PubMedView ArticleGoogle Scholar
  50. Okada Y, Yamaguchi K, Nakajima T, Nishikawa T, Jo M, Mitsumoto Y, Kimura H, Nishimura T, Tochiki N, Yasui K, et al. Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats. Liver Int. 2013;33:301–11.PubMedView ArticleGoogle Scholar
  51. Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis. 1985;57:65–73.PubMedView ArticleGoogle Scholar
  52. Schreyer SA, Wilson DL, LeBoeuf RC. C57BL/6 mice fed high fat diets as models for diabetes-accelerated atherosclerosis. Atherosclerosis. 1998;136:17–24.PubMedView ArticleGoogle Scholar
  53. Paigen B, Mitchell D, Reue K, Morrow A, Lusis AJ, LeBoeuf RC. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A. 1987;84:3763–7.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.PubMedPubMed CentralView ArticleGoogle Scholar
  55. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343–53.PubMedView ArticleGoogle Scholar
  56. Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–37.PubMedView ArticleGoogle Scholar
  57. Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16.PubMedGoogle Scholar
  58. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–30.PubMedView ArticleGoogle Scholar
  59. Plump AS, Breslow JL. Apolipoprotein E and the apolipoprotein E-deficient mouse. Annu Rev Nutr. 1995;15:495–518.PubMedView ArticleGoogle Scholar
  60. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1994;91:9607–11.PubMedPubMed CentralView ArticleGoogle Scholar
  61. Paszty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994;94:899–903.PubMedPubMed CentralView ArticleGoogle Scholar
  62. Ghiselli G, Schaefer EJ, Gascon P, Breser Jr HB. Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science. 1981;214:1239–41.PubMedView ArticleGoogle Scholar
  63. Smith JD, Breslow JL. The emergence of mouse models of atherosclerosis and their relevance to clinical research. J Intern Med. 1997;242:99–109.PubMedView ArticleGoogle Scholar
  64. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994;14:133–40.PubMedView ArticleGoogle Scholar
  65. Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler Thromb. 1994;14:141–7.PubMedView ArticleGoogle Scholar
  66. Pendse AA, Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N. Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond. J Lipid Res. 2009;50:S178–82.PubMedPubMed CentralView ArticleGoogle Scholar
  67. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Investig. 1999;103:1579–86.PubMedPubMed CentralView ArticleGoogle Scholar
  68. Getz GS, Reardon CA. Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall. J Lipid Res. 2009;50(Suppl):S156–161.PubMedPubMed CentralGoogle Scholar
  69. Klotz S, Hay I, Zhang G, Maurer M, Wang J, Burkhoff D. Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction. Hypertension. 2006;47:901–11.PubMedView ArticleGoogle Scholar
  70. Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:1104–15.PubMedPubMed CentralView ArticleGoogle Scholar
  71. Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993;92:883–93.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Merat S, Casanada F, Sutphin M, Palinski W, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but Do Not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels Are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol. 1999;19:1223–30.PubMedView ArticleGoogle Scholar
  73. Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990;24:133–70.PubMedView ArticleGoogle Scholar
  74. VanderLaan PA, Reardon CA, Thisted RA, Getz GS. VLDL best predicts aortic root atherosclerosis in LDL receptor deficient mice. J Lipid Res. 2009;50:376–85.PubMedPubMed CentralView ArticleGoogle Scholar
  75. Tian J, Pei H, Sanders JM, Angle JF, Sarembock IJ, Matsumoto AH, Helm GA, Shi W. Hyperlipidemia is a major determinant of neointimal formation in LDL receptor-deficient mice. Biochem Biophys Res Commun. 2006;345:1004–9.PubMedView ArticleGoogle Scholar
  76. Ali ZA, Alp NJ, Lupton H, Arnold N, Bannister T, Hu Y, Mussa S, Wheatcroft M, Greaves DR, Gunn J, Channon KM. Increased in-stent stenosis in ApoE knockout mice: insights from a novel mouse model of balloon angioplasty and stenting. Arterioscler Thromb Vasc Biol. 2007;27:833–40.PubMedView ArticleGoogle Scholar
  77. Herijgers N, Van Eck M, Groot PHE, Hoogerbrugge PM, Van Berkel TJC. Effect of bone marrow transplantation on lipoprotein metabolism and atherosclerosis in LDL receptor-knockout mice. Arterioscler Thromb Vasc Biol. 1997;17:1995–2003.PubMedView ArticleGoogle Scholar
  78. Merat S, Fruebis J, Sutphin M, Silvestre M, Reaven PD. Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis. J Gerontol A Biol Sci Med Sci. 2000;55:B85–94.PubMedView ArticleGoogle Scholar
  79. Ma Y, Wang W, Zhang J, Lu Y, Wu W, Yan H, Wang Y. Hyperlipidemia and atherosclerotic lesion development in ldlr-deficient mice on a long-term high-Fat diet. PLoS One. 2012;7:e35835.PubMedPubMed CentralView ArticleGoogle Scholar
  80. Perlman RL. Mouse models of human disease: an evolutionary perspective. Evol Med Public Health. 2016;2016:170–6.PubMedPubMed CentralGoogle Scholar
  81. Murray SA, Morgan JL, Kane C, Sharma Y, Heffner CS, Lake J, Donahue LR. Mouse gestation length is genetically determined. PLoS One. 2010;5:e12418.PubMedPubMed CentralView ArticleGoogle Scholar
  82. Bentzon JF, Falk E. Atherosclerotic lesions in mouse and man: is it the same disease? Curr Opin Lipidol. 2010;21:434–40.PubMedView ArticleGoogle Scholar
  83. Bennett BJ, Davis RC, Civelek M, Orozco L, Wu J, Qi H, Pan C, Packard RRS, Eskin E, Yan M, et al. Genetic architecture of atherosclerosis in mice: a systems genetics analysis of common inbred strains. PLoS Genet. 2015;11:e1005711.PubMedPubMed CentralView ArticleGoogle Scholar
  84. Vergeer M, Holleboom AG, Kastelein JJP, Kuivenhoven JA. The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis? J Lipid Res. 2010;51:2058–73.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Hayek T, Azrolan N, Verdery RB, Walsh A, Chajek-Shaul T, Agellon LB, Tall AR, Breslow JL. Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice. J Clin Invest. 1993;92:1143–52.PubMedPubMed CentralView ArticleGoogle Scholar
  86. Bullock BC, Clarkson TB, Lehner ND, Lofland Jr HB, St Clair RW. Atherosclerosis in cebus albifrons monkeys. [. clinical and pathologic studies. Exp Mol Pathol. 1969;10:39–62.PubMedView ArticleGoogle Scholar
  87. Whitman SC. A Practical Approach to Using Mice in Atherosclerosis Research. Clin Biochem Rev. 2004;25:81–93.PubMedPubMed CentralGoogle Scholar
  88. Singh V, Tiwari RL, Dikshit M, Barthwal MK. Models to study atherosclerosis: a mechanistic insight. Curr Vasc Pharmacol. 2009;7:75–109.PubMedView ArticleGoogle Scholar
  89. Parasuraman S, Raveendran R, Kesavan R. Blood sample collection in small laboratory animals. J Pharmacol Pharmacother. 2010;1:87–93.PubMedPubMed CentralView ArticleGoogle Scholar
  90. Kostamaa H, Donovan J, Kasaoka S, Tobis J, Fitzpatrick L. Calcified plaque cross-sectional area in human arteries: correlation between intravascular ultrasound and undecalcified histology. Am Heart J. 1999;137:482–8.PubMedView ArticleGoogle Scholar
  91. Ritman EL, Lerman A. The dynamic vasa vasorum. Cardiovasc Res. 2007;75:649–58.PubMedPubMed CentralView ArticleGoogle Scholar
  92. Rosenfeld ME, Averill MM, Bennett BJ, Schwartz SM. Progression and disruption of advanced atherosclerotic plaques in murine models. Curr Drug Targets. 2008;9:210–6.PubMedPubMed CentralView ArticleGoogle Scholar
  93. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, Narula J. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;25:2054–61.PubMedView ArticleGoogle Scholar
  94. Williams H, Johnson JL, Carson KG, Jackson CL. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2002;22:788–92.PubMedView ArticleGoogle Scholar
  95. Johnson J, Carson K, Williams H, Karanam S, Newby A, Angelini G, George S, Jackson C. Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment. Circulation. 2005;111:1422–30.PubMedView ArticleGoogle Scholar
  96. Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:1470–6.PubMedView ArticleGoogle Scholar
  97. Minamino T, Kitakaze M. ER stress in cardiovascular disease. J Mol Cell Cardiol. 2010;48:1105–10.PubMedView ArticleGoogle Scholar
  98. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013–30.PubMedView ArticleGoogle Scholar
  99. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32.PubMedView ArticleGoogle Scholar
  100. Tsang KY, Chan D, Bateman JF, Cheah KS. In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences. J Cell Sci. 2010;123:2145–54.PubMedView ArticleGoogle Scholar
  101. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 2007;116:1226–33.PubMedView ArticleGoogle Scholar
  102. Tabas I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res. 2010;107:839–50.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Hotamisligil GS. Endoplasmic reticulum stress and atherosclerosis. Nat Med. 2010;16:396–9.PubMedPubMed CentralView ArticleGoogle Scholar
  104. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–61.PubMedView ArticleGoogle Scholar
  105. Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature. 2005;438:612–21.PubMedView ArticleGoogle Scholar
  106. Zhou J, Lhotak S, Hilditch BA, Austin RC. Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation. 2005;111:1814–21.PubMedView ArticleGoogle Scholar
  107. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab. 2009;9:474–81.PubMedPubMed CentralView ArticleGoogle Scholar
  108. Tsukano H, Gotoh T, Endo M, Miyata K, Tazume H, Kadomatsu T, Yano M, Iwawaki T, Kohno K, Araki K, et al. The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2010;30:1925–32.PubMedView ArticleGoogle Scholar
  109. Schrijvers DM, De Meyer GR, Herman AG, Martinet W. Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res. 2007;73:470–80.PubMedView ArticleGoogle Scholar
  110. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005;25:2255–64.PubMedView ArticleGoogle Scholar
  111. Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type a scavenger receptor. J Cell Biol. 2005;171:61–73.PubMedPubMed CentralView ArticleGoogle Scholar
  112. Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, Koschinsky ML, Harkewicz R, Witztum JL, Tsimikas S, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12:467–82.PubMedPubMed CentralView ArticleGoogle Scholar
  113. Li G, Scull C, Ozcan L, Tabas I. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol. 2010;191:1113–25.PubMedPubMed CentralView ArticleGoogle Scholar
  114. Zeng L, Zampetaki A, Margariti A, Pepe AE, Alam S, Martin D, Xiao Q, Wang W, Jin ZG, Cockerill G, et al. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc Natl Acad Sci U S A. 2009;106:8326–31.PubMedPubMed CentralView ArticleGoogle Scholar
  115. Civelek M, Manduchi E, Riley RJ, Stoeckert Jr CJ, Davies PF. Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ Res. 2009;105:453–61.PubMedPubMed CentralView ArticleGoogle Scholar
  116. Dong Y, Zhang M, Wang S, Liang B, Zhao Z, Liu C, Wu M, Choi HC, Lyons TJ, Zou MH. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes. 2010;59:1386–96.PubMedPubMed CentralView ArticleGoogle Scholar
  117. Zhou J, Werstuck GH, Lhotak S, de Koning AB, Sood SK, Hossain GS, Moller J, Ritskes-Hoitinga M, Falk E, Dayal S, et al. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation. 2004;110:207–13.PubMedView ArticleGoogle Scholar
  118. Kedi X, Ming Y, Yongping W, Yi Y, Xiaoxiang Z. Free cholesterol overloading induced smooth muscle cells death and activated both ER- and mitochondrial-dependent death pathway. Atherosclerosis. 2009;207:123–30.PubMedView ArticleGoogle Scholar
  119. Pedruzzi E, Guichard C, Ollivier V, Driss F, Fay M, Prunet C, Marie JC, Pouzet C, Samadi M, Elbim C, et al. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol. 2004;24:10703–17.PubMedPubMed CentralView ArticleGoogle Scholar
  120. Cheang WS, Tian XY, Wong WT, Lau CW, Lee SS, Chen ZY, Yao X, Wang N, Huang Y. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5’ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway. Arterioscler Thromb Vasc Biol. 2014;34:830–6.PubMedView ArticleGoogle Scholar
  121. Wong WT, Tian XY, Huang Y. Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2-derived prostanoids. J Cardiovasc Pharmacol. 2013;61:204–14.PubMedView ArticleGoogle Scholar
  122. Zhang Y, Liu J, Luo JY, Tian XY, Cheang WS, Xu J, Lau CW, Wang L, Wong WT, Wong CM, et al. Upregulation of angiotensin (1–7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes. Antioxid Redox Signal. 2015;23:880–92.PubMedPubMed CentralView ArticleGoogle Scholar
  123. Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, Jin L, Lian Q, Huang Y, Ding H, et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation. 2015;131:1861–71.PubMedPubMed CentralView ArticleGoogle Scholar
  124. Xu A, Huang Y. A Tireless Giant in Vascular Research. J Cardiovasc Pharmacol. 2016;67(5):359–60.PubMedView ArticleGoogle Scholar
  125. Dikalov S. Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med. 2011;51:1289–301.PubMedPubMed CentralView ArticleGoogle Scholar
  126. Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem. 1955;217:409–27.PubMedGoogle Scholar
  127. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002;277:44784–90.PubMedView ArticleGoogle Scholar
  128. Tahara EB, Navarete FD, Kowaltowski AJ. Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med. 2009;46:1283–97.PubMedView ArticleGoogle Scholar
  129. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci. 2004;24:7779–88.PubMedView ArticleGoogle Scholar
  130. Brand MD. The sites and topology of mitochondrial superoxide production. Exp Gerontol. 2010;45:466–72.PubMedPubMed CentralView ArticleGoogle Scholar
  131. Panov A, Dikalov S, Shalbuyeva N, Hemendinger R, Greenamyre JT, Rosenfeld J. Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol. 2007;292:C708–718.PubMedView ArticleGoogle Scholar
  132. Nazarewicz RR, Dikalova AE, Bikineyeva A, Dikalov SI. Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress. Am J Physiol Heart Circ Physiol. 2013;305:H1131–1140.PubMedPubMed CentralView ArticleGoogle Scholar
  133. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909–50.PubMedPubMed CentralView ArticleGoogle Scholar
  134. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 2000;192:1001–14.PubMedPubMed CentralView ArticleGoogle Scholar
  135. Leonarduzzi G, Chiarpotto E, Biasi F, Poli G. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Mol Nutr Food Res. 2005;49:1044–9.PubMedView ArticleGoogle Scholar
  136. Lee JY, Jung GY, Heo HJ, Yun MR, Park JY, Bae SS, Hong KW, Lee WS, Kim CD. 4-Hydroxynonenal induces vascular smooth muscle cell apoptosis through mitochondrial generation of reactive oxygen species. Toxicol Lett. 2006;166:212–21.PubMedView ArticleGoogle Scholar
  137. Di Lisa F, Canton M, Menabo R, Dodoni G, Bernardi P. Mitochondria and reperfusion injury. The role of permeability transition. Basic Res Cardiol. 2003;98:235–41.PubMedGoogle Scholar
  138. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res. 2004;61:372–85.PubMedView ArticleGoogle Scholar
  139. Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N Y Acad Sci. 2005;1047:248–58.PubMedView ArticleGoogle Scholar
  140. Vindis C, Elbaz M, Escargueil-Blanc I, Augé N, Heniquez A, Thiers J-C, Nègre-Salvayre A, Salvayre R. Two distinct calcium-dependent mitochondrial pathways Are involved in oxidized LDL-induced apoptosis. Arterioscler Thromb Vasc Biol. 2005;25:639–45.PubMedView ArticleGoogle Scholar
  141. Yao PM, Tabas I. Free cholesterol loading of macrophages is associated with widespread mitochondrial dysfunction and activation of the mitochondrial apoptosis pathway. J Biol Chem. 2001;276:42468–76.PubMedView ArticleGoogle Scholar
  142. Asmis R, Begley JG. Oxidized LDL promotes peroxide-mediated mitochondrial dysfunction and cell death in human macrophages: a caspase-3-independent pathway. Circ Res. 2003;92:e20–29.PubMedView ArticleGoogle Scholar
  143. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417–23.PubMedView ArticleGoogle Scholar
  144. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309:481–4.PubMedView ArticleGoogle Scholar
  145. Ballinger SW, Patterson C, Knight-Lozano CA, Burow DL, Conklin CA, Hu Z, Reuf J, Horaist C, Lebovitz R, Hunter GC, et al. Mitochondrial integrity and function in atherogenesis. Circulation. 2002;106:544–9.PubMedView ArticleGoogle Scholar
  146. Yu E, Baker L, Harrison J, Figg N, Mercer J, Calvert P, Vidal-Puig A, Murphy M, Bennett M. Mitochondrial DNA damage promotes atherosclerosis and is associated with vulnerable plaque. Lancet. 2013;381:S117.View ArticleGoogle Scholar
  147. Yu E, Calvert PA, Mercer JR, Harrison J, Baker L, Figg NL, Kumar S, Wang JC, Hurst LA, Obaid DR, et al. Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans. Circulation. 2013;128:702–12.PubMedView ArticleGoogle Scholar
  148. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7.PubMedPubMed CentralView ArticleGoogle Scholar
  149. Levine GN, Chodos AP, Loscalzo J. Restenosis following coronary angioplasty: clinical presentations and therapeutic options. Clin Cardiol. 1995;18:693–703.PubMedView ArticleGoogle Scholar
  150. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998;97:916–31.PubMedView ArticleGoogle Scholar
  151. Schwartz SM, deBlois D, O’Brien ER. The intima. Soil for atherosclerosis and restenosis. Circ Res. 1995;77:445–65.PubMedView ArticleGoogle Scholar
  152. Tse G, Yan BP, Chan YW, Tian XY, Huang Y. Reactive oxygen species, endoplasmic reticulum stress and mitochondrial dysfunction: the link with cardiac arrhythmogenesis. Front Physiol. 2016;7:313.PubMedPubMed CentralGoogle Scholar
  153. Thyberg J, Blomgren K, Hedin U, Dryjski M. Phenotypic modulation of smooth muscle cells during the formation of neointimal thickenings in the rat carotid artery after balloon injury: an electron-microscopic and stereological study. Cell Tissue Res. 1995;281:421–33.PubMedView ArticleGoogle Scholar
  154. Xu Q. Mouse models of arteriosclerosis: from arterial injuries to vascular grafts. Am J Pathol. 2004;165:1–10.PubMedPubMed CentralView ArticleGoogle Scholar
  155. Napoli C, Lerman LO. Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia. Mayo Clin Proc. 2001;76:619–31.PubMedView ArticleGoogle Scholar
  156. House SJ, Potier M, Bisaillon J, Singer HA, Trebak M. The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch. 2008;456:769–85.PubMedPubMed CentralView ArticleGoogle Scholar
  157. Munaron L, Antoniotti S, Fiorio Pla A, Lovisolo D. Blocking Ca2 + entry: a way to control cell proliferation. Curr Med Chem. 2004;11:1533–43.PubMedView ArticleGoogle Scholar
  158. Miller BA. The role of TRP channels in oxidative stress-induced cell death. J Membr Biol. 2006;209:31–41.PubMedView ArticleGoogle Scholar
  159. Tano J-YK, Lee RH, Vazquez G. Macrophage function in atherosclerosis: potential roles of TRP channels. Channels. 2012;6:141–8.PubMedPubMed CentralView ArticleGoogle Scholar
  160. Ingueneau C, Huynh UD, Marcheix B, Athias A, Gambert P, Negre-Salvayre A, Salvayre R, Vindis C. TRPC1 is regulated by caveolin-1 and is involved in oxidized LDL-induced apoptosis of vascular smooth muscle cells. J Cell Mol Med. 2009;13:1620–31.PubMedView ArticleGoogle Scholar
  161. Ru X, Zheng C, Zhao Q, Lan H-Y, Huang Y, Wan S, Mori Y, Yao X. Transient receptor potential channel M2 contributes to neointimal hyperplasia in vascular walls. Biochim Biophys Acta (BBA) Mol Basis Dis. 2015;1852:1360–71.View ArticleGoogle Scholar
  162. Kumar B, Dreja K, Shah SS, Cheong A, Xu SZ, Sukumar P, Naylor J, Forte A, Cipollaro M, McHugh D, et al. Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia. Circ Res. 2006;98:557–63.PubMedPubMed CentralView ArticleGoogle Scholar
  163. Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res. 2016;118:703–20.PubMedView ArticleGoogle Scholar
  164. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24.PubMedView ArticleGoogle Scholar
  165. Neth P, Nazari-Jahantigh M, Schober A, Weber C. MicroRNAs in flow-dependent vascular remodelling. Cardiovasc Res. 2013;99:294–303.PubMedView ArticleGoogle Scholar
  166. Qin X, Wang X, Wang Y, Tang Z, Cui Q, Xi J, Li YS, Chien S, Wang N. MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A. 2010;107:3240–4.PubMedPubMed CentralView ArticleGoogle Scholar
  167. Wang KC, Garmire LX, Young A, Nguyen P, Trinh A, Subramaniam S, Wang N, Shyy JY, Li YS, Chien S. Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc Natl Acad Sci U S A. 2010;107:3234–9.PubMedPubMed CentralView ArticleGoogle Scholar
  168. Fang Y, Shi C, Manduchi E, Civelek M, Davies PF. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci U S A. 2010;107:13450–5.PubMedPubMed CentralView ArticleGoogle Scholar
  169. Chen LJ, Chuang L, Huang YH, Zhou J, Lim SH, Lee CI, Lin WW, Lin TE, Wang WL, Chen L, et al. MicroRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress. Circ Res. 2015;116:1157–69.PubMedPubMed CentralView ArticleGoogle Scholar
  170. Ma S, Tian XY, Zhang Y, Mu C, Shen H, Bismuth J, Pownall HJ, Huang Y, Wong WT. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis. Sci Rep. 2016;6:22910.PubMedPubMed CentralView ArticleGoogle Scholar
  171. Wang J, Kang YX, Pan W, Lei W, Feng B, Wang XJ. Enhancement of Anti-Inflammatory Activity of Curcumin Using Phosphatidylserine-Containing Nanoparticles in Cultured Macrophages. Int J Mol Sci. 2016;17(5):E969. doi:10.3390/ijms17060969.
  172. Taniguchi R, Miura Y, Koyama H, Chida T, Anraku Y, Kishimura A, Shigematsu K, Kataoka K, Watanabe T. Adequately-sized nanocarriers allow sustained targeted drug delivery to neointimal lesions in Rat arteries. Mol Pharm. 2016;13:2108–16.PubMedView ArticleGoogle Scholar
  173. Tse G, Lai ET, Yeo JM, Yan BP. Electrophysiological mechanisms of Bayés syndrome: insights from clinical and mouse studies. Front Physiol. 2016;7:188.PubMedPubMed CentralGoogle Scholar
  174. Tse G, Lai ET, Lee AP, Yan BP, Wong SH. Electrophysiological mechanisms of gastrointestinal arrhythmogenesis: lessons from the heart. Front Physiol. 2016;7:230.PubMedPubMed CentralGoogle Scholar
  175. Tse G, Lai ET, Chan YW, Yeo JM, Yan BP. What is the arrhythmic substrate in viral myocarditis? insights from clinical and animal studies. Front Physiol. 2016;7:308.PubMedPubMed CentralGoogle Scholar
  176. Chatzigeorgiou A, Halapas A, Kalafatakis K, Kamper E. The use of animal models in the study of diabetes mellitus. In Vivo. 2009;23:245–58.PubMedGoogle Scholar
  177. Leong XF, Ng CY, Jaarin K. Animal models in cardiovascular research: hypertension and atherosclerosis. Biomed Res Int. 2015;2015:528757.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

© The Author(s). 2017