Mining literature for a comprehensive pathway analysis: A case study for retrieval of homocysteine related genes for genetic and epigenetic studies
© Sharma et al; licensee BioMed Central Ltd. 2006
Received: 15 November 2005
Accepted: 23 January 2006
Published: 23 January 2006
Homocysteine is an independent risk factor for cardiovascular diseases. It is also known to be associated with a variety of complex disorders. While there are a large number of independent studies implicating homocysteine in isolated pathways, the mechanism of homocysteine induced adverse effects are not clear. Homocysteine-induced modulation of gene expression through alteration of methylation status or by hitherto unknown mechanisms is predicted to lead to several pathological conditions either directly or indirectly. In the present manuscript, using literature mining approach, we have identified the genes that are modulated directly or indirectly by an elevated level of homocysteine. These genes were then placed in appropriate pathways in an attempt to understand the molecular basis of homocysteine induced complex disorders and to provide a resource for selection of genes for polymorphism screening and analysis of mutations as well as epigenetic modifications in relation to hyperhomocysteinemia. We have identified 135 genes in 1137 abstracts that either modulate the levels of homocysteine or are modulated by elevated levels of homocysteine. Mapping the genes to their respective pathways revealed that an elevated level of homocysteine leads to the atherosclerosis either by directly affecting lipid metabolism and transport or via oxidative stress and/or Endoplasmic Reticulum (ER) stress. Elevated levels of homocysteine also decreases the bioavailability of nitric oxide and modulates the levels of other metabolites including S-adenosyl methionine and S-adenosyl homocysteine which may result in cardiovascular or neurological disorders. The ER stress emerges as the common pathway that relates to apoptosis, atherosclerosis and neurological disorders and is modulated by levels of homocysteine. The comprehensive network collated has lead to the identification of genes that are modulated by homocysteine indicating that homocysteine exerts its effect not only through modulating the substrate levels for various catalytic processes but also through regulation of expression of genes involved in complex diseases.
Although hyperhomocysteinemia has been associated with several diseases, the mechanism of homocysteine-induced deleterious effects is not fully elucidated. Prominent among the various mechanism proposed for the harmful effects of homocysteine is its ability to modulate the expression of certain genes that may either directly or indirectly lead to several pathological conditions . Homocysteine-induced modulation of gene expression may be due to altered methylation status as the levels of SAH, an inhibitor of many SAM-dependent methyl transferases (Mtase) are elevated during hyperhomocysteinemic conditions [12, 13]. Apart from the modulation of gene expression due to altered methylation, homocysteine might modulate gene expression by hitherto unknown mechanisms .
List of genes identified by literature mining that are modulated by elevated level of homocysteine
Renin – Angiotensin
S-adenosylhomocysteine hydrolase – like
BCL2-associated × protein
B-cell cll/lymphoma 2
Protein regulated by oxygen 1
Chemokine receptor 2
Cyclin-dependent kinase 2
Cholesteryl ester transfer protein
Calcitonin gene related peptide
Myc proto-oncogene protein
C-type natriuretic peptide
C-AMP receptor protein
Vitamin B12 Transport
Integral to plasma membrane/Signaling
Chloride ion channel gene
DNA Methyltransferase 1
DNA Methyltransferase 2
DNA Methyltransferase 3
Extracellular Signal-Regulated Kinase 2
Focal adhesion kinase
Glutamic acid decarboxylase 67
Glutamic acid decarboxylase 153
Glutamic acid decarboxylase 45
GATA-Binding Protein 4
GS homeobox 1
Glucose related protein 78
Glucose related protein 98
Inhibitor Of Kappa Light Chain Gene Enhancer
Inducible Nitric Oxide Synthase
Nitric oxide stress
Low Density Lipoprotein Receptor
Lectin like oxidized LDL receptor-1
Monocyte Chemoattractant Protein 1
Methyl-CpG-Binding Domain Protein 2
Methylation binding protein
Methyl-CpG-Binding Protein 2
Methylation binding protein
Mitogen-Activated Protein Kinase Kinase
Matrix metalloproteinase 3
Remodeling of extracellular matrix
Methyl Thioadenosine Phosphorylase
Nuclear Factor Kappa-B
Nitric Oxide Synthase 2
Nitric oxide Synthesis
Serine /threonine protein kinase belong to MAPK subfamily
Tumor protein p53
Plasminogen Activator Inhibitor-1
Peptidylglycine alpha-amidating monooxygenase
Neuro peptide amidation
Platelet-derived growth factor
Phosphatidylethanolamine (PE) N-Methyltransferase
Methylation of PE
Protein kinase C
Peroxisome Proliferator-Activated Receptor-Alpha
Protein Arginine N-Methyltransferase
Ribosomal protein S3A
Structural constituent of Ribosome
smooth muscle-associated protein 8
sterol regulatory element binding protein-1
T-cell death-associated gene 51
Transforming growth factor beta
tumor necrosis factor alpha
Tumor necrosis factor receptor 2 gene
Tissue Inhibitor Of Metalloproteinase 1
Tissue-type plasminogen activator
Vascular Cell Adhesion Molecule 1
Yin Yang 1
Coagulation factor II
N5-glutamine AdoMet-dependent methyltransferase
ATP-Binding Cassette subfamily C
Cellular cisplatin transporter.
Angiotensin converting enzyme
Renin – Angiotensin
arylamine N-acetyltransferase type-1
Detoxification of a plethora of hydrazine and arylamine drugs
Super Oxide Dismutase
Activating transcription factor
List of genes identified by literature mining that modulate homocysteine levels
Conversion of 5, 10-methylene-tetrahydrofolate to 5-methyl-tetrahydrofolate.
Condensation of homo-cysteine and serine to form cystathionine
Remethylation of homocysteine to methionine
Methionine synthase reductase
Reductive regeneration of cob(I)alamin cofactor required for the maintenance of MTR in a functional state
5-methyl-tetrahydrofolate internalization in cell
Glutamate Carboxypeptidase II
Polyglutamate converted to monoglutamate folate by action of the enzyme folylpoly gammaglutamate carboxy-peptidase (FGCPI), an enzyme expressed by GCPII.
Endothelial Nitric oxide synthase
Conversion of L-Arginine to L-Citrulline and nitric oxide synthase (NO)
Transport of vitamin B12
Serine Hydroxymethyltransferase 1
Reversible conversion of serine and tetrahydrofolate to glycine and 5, 10-methylene tetrahydrofolate.
5, 10-methylene THF and deoxyuridylate to form dihydro-folate and thymidylate.
Hydrolysis of cystathionine to cysteine and α-Ketoglutarate
Methylene-tetra hydrofolate dehydrogenase
Conversion of 5, 10-methylene-tetrahydrofolate to5, 10methenyl-tetrahydrofolate.
Conversion of 5-formyltetrahydrofolate to 5, 10-methenyltetrahydrofolate.
Mediates the binding, internalization, and catabolism of lipoprotein particles.
Vascular endothelial growth factor
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth.
Hydrolyzes the toxic organo-phosphorus. It also mediate an enzymatic protection of LDL against oxidative modification.
In Liver & kidney it catalyses the conversion of betaine to dimethyl glycine (DMG).
Methionine Adenosyltransferase 1A
Methionine to SAM by transfer of the adenosyl moiety of ATP to the sulfur atom of methionine
Hydrolysis of AdoHcy to adenosine and homocysteine
Cystathionine beta lyase
Conversion of cystathionine to homocysteine.
Coagulation factor V
Cofactor for the factor Xa-catalyzed activation of prothrombin to the clotting enzyme thrombin.
Prothrombin activator inhibitor-1
Inhibition of fibrinolysis by inhibiting the plasminogen-activator and t-PA.
Physiological processes that are affected due to homocysteine-induced modulation of gene expression
Elevated homocysteine levels and oxidative stress
Hyperhomocysteinemia has also been reported to be associated albeit indirectly with hypoxic conditions. Supporting this is the expression of Cap43 [that codes for a 43 kDa protein associated with hypoxia in endothelial cells (EC)] in cells treated with homocysteine. Hypoxia in alveoli leads to damage of capillary wall, a condition predisposing for atherosclerosis. Furthermore, it has also been shown that there is a decrease in the MAT1A transcription and mRNA stability in cultured hepatocytes exposed to hypoxic conditions .
Mechanisms mediating the anti-atherosclerotic effect of nitric oxide
Anti-atherosclerotic effect of nitric oxide
Promotion of SMC proliferation
Inhibition of platelet aggregation
Reduction in endothelial activation & Inhibition of MCP-1
Stabilizes NF-Kβ inhibitor, Ikβα
Inhibition of LDL oxidation & lipid peroxidation
Reduces super oxide generation
Decrease the Expression of PAI-1
Nitric oxide regulates vascular cell adhesion molecule 1 gene expression
Another potential mechanism for the decreased bioavailability of NO in hyperhomocysteinemic states is the increased generation of asymmetric dimethylarginine (ADMA), an analogue of L-arginine, which is a competitive inhibitor of eNOS . ADMA also promotes the "uncoupling" of eNOS (Figure 2) leading to increased production of superoxide & other reactive oxygen species, which may cause further decrease in availability of NO. ADMA is produced during degradation of proteins containing methylated arginine residues by protein arginine N- methyltransferases (PRMTs) . The increased SAM dependent generation of these methylated proteins, results in both increased production of ADMA and increased generation of homocysteine . The inhibition of endothelial nitric oxide synthesis by ADMA impairs cerebral blood flow, which may contribute to the development of Alzheimer's disease .
Furthermore, one of the mechanisms proposed for the anti-thrombotic effect of NO is its ability to inhibit the expression of the prothrombotic protein PAI-1. It has also been shown that NO released from activated platelets inhibits the recruitment of platelets to the growing thrombus . Thus decrease in NO concentration may result in increased expression of PAI-1 and platelet aggregation leading to thrombosis.
Intracellular oxidative stress may be either due to excessive generation of reactive oxygen species or to decreased ability of cells to scavenge the reactive oxygen species leading to its accumulation. We propose that homocysteine-induced oxidative stress is primarily due to the decreased ability of the cells to detoxify H2O2 & other lipid peroxides due to decreased activity of intracellular antioxidant enzymes. Furthermore, decreased bioavailability of nitric oxide may lead to the increased expression of pro-inflammatory cytokines and PAI which can potentially lead to cardiovascular diseases.
Hyperhomocysteinemia: apoptosis and inflammatory pathways
However, exposure to excess ER stress results in apoptotic cell death. ER stress activates c-Jun N-terminal kinases (JNKs) that regulate gene expression via phosphorylation and activation of transcription factors such as c-JUN. The activation of JNK is mediated by TNF receptor-associated factor-2 (TRAF2), which transduce signals from IREs that act as stress sensors and initiates UPR . TRAF2 activates the apoptosis-signaling kinase (ASK1) or MAPKKK (mitogen activated protein kinase kinase kinase). Activation of MAPKKK leads to activation of JNK protein kinase that in turn causes apoptosis . The TRAF1 binds to the TRADD (TNFR-Associated Death Domain), which recruits the activated caspase 8 initiating a proteolytic cascade subsequently resulting in apoptosis. Furthermore, caspase 8 also leads to release of pro-apoptotic factor cytochrome C . Homocysteine may induce oxidative stress and apoptosis through an NADPH oxidase and/or JNK-dependent mechanism(s) . Extra cellular adenosine (Ado) along with homocysteine (Ado/Hcy) causes apoptosis of cultured pulmonary artery endothelial cells through the enhanced formation of intracellular S-adenosylhomocysteine (Figure 3, branch 1). SAH inhibits isoprenylcysteine carboxylmethyltransferase (ICMT), which results in decrease of Ras methylation and activation of downstream signaling molecules resulting in apoptosis. ICMT catalyzes the posttranslational methylation of isoprenylated C-terminal cysteine residues found in many signaling proteins such as small monomeric G proteins [48, 49]. Similarly high concentration of adenosine results in apoptosis of L1210 lymphocytic leukemia cells. Apoptosis in these cells was preceded by an early but transient expression of the proto-oncogene c-myc .
Expression of c-myc sensitizes cells to a wide range of pro-apoptotic insults that include DNA damage, hypoxia and nutrient deprivation (Figure 3, branch 2). The pro -apoptotic effect of c-myc is mediated through the release of cytochrome C into the cytosol . Holocytochrome C interacts with apoptotic protease activating factor (APAF-1), which then recruits and activates procaspase 9. This ternary complex triggers the autocatalytic processing of caspase 9 and subsequently activates caspase 3. However inhibition of CD95 and P53 signaling pathway does not block this release, but activation of the caspase dependent apoptotic machinery requires cooperation between c-myc induced cytochrome C release and CD95 signaling. Thus, c-myc induction leads to release of cytochrome C to the cytosol recruiting the cells to other apoptotic triggers like CD95 pathway or p53 activation. C-myc might also induce apoptosis through active response factor (ARF) expression via activation of P53 . Recently it has been shown that homocysteine induced apoptosis in human umbilical vein endothelial cells is correlated with p53 dependent Noxa expression . The expression of the Noxa gene involves direct activation of its promoter by p53. Interestingly, the activity of p53 is regulated through lysine methylation. Methylated p53 is restricted to the nucleus and has increased stability. The "hyper-stabilization" and activation of p53 result in cell cycle arrest and apoptosis . The methyltransferase activity is critical for p53 dependent apoptosis. Thus, it can be perceived that in hyperhomocysteinemic state p53 lysine methylation could be inhibited. Homocysteine could also potentially inhibit endothelial cell growth by inhibiting the expression of cyclin A mRNA. Apart from cyclin A associated kinase activity, cyclin dependent kinase (CDK2) activity was also significantly inhibited . Interestingly, stress induced activation of P53 promotes transcription of P21, which in turn binds to CDKs and leads to blocking of the G1 to S phase transition during cell cycle.
Homocysteine affects mitogenesis in a cell type specific manner. Although elevated levels of homocysteine lead to apoptosis and has growth inhibitory effect on endothelial cells, it leads to proliferation of smooth muscle cells eg. homocysteine enhances AP-1 activity in A7r5 aortic smooth muscle cells thus influencing cell proliferation . In a recent report it was shown that elevated levels of homocysteine result in increased AP-1 nuclear protein binding, cell DNA synthesis and proliferation in mesangial cells by increasing Erk activity via a calcium-dependent mechanism [, Figure 3, branch 5]. Furthermore, homocysteine has been reported to up regulate the expression of VEGF mRNA in pigmented human endothelial cell line via ATF4 mediated activation. . The cell survival signal from VEGF is mainly brought about by P13-mediated activation of Akt/PKB. The downstream targets for Akt/PKB pathway inhibit apoptosis. Furthermore, VEGF also leads to the induction of Raf-MEK -ERK pathway in human umbilical endothelial cells (HUVECs) relating to cell survival .
Apart from activating the unfolded protein response, homocysteine-induced ER stress also activates the sterol regulatory binding proteins (SREBPs). Homocysteine induces the expression of sterol regulatory element binding protein-1 (SREBP1, Figure 3), an ER membrane bound transcription factor, in cultured vascular endothelial cells and human hepatocyte leading to increased biosynthesis and uptake of cholesterol, triglycerides and accumulation of intracellular cholesterol [60, 61]. Normally the expression and activity of SREBPs is regulated by SREBP cleavage activation protein (SCAP). However, it is believed that homocysteine circumvents this mechanism, maintaining the cells in sterol-starved state although lipids continue to accumulate.
Thus by mapping the genes (identified using literature based search) in appropriate pathway, we show that elevated levels of homocysteine cause the up regulation of ER stress proteins resulting in apoptosis. Homocysteine might also mediate apoptosis via P53 mediated pathway or by inhibition of methyl transferases like ICMT. Furthermore, ER stress also leads to altered lipid metabolism which may lead to cardiovascular disorders. Thus, homocysteine-induced ER stress emerges as the common pathway that relates to apoptosis and atherosclerosis. In this context it needs to be mentioned that homocysteine can potentially cleave critical protein disulfide bonds resulting in the alteration of structure and/or function of the protein [62–64]. It can be perceived that this might also lead to protein misfolding /unfolding which is a hallmark of ER stress.
Hyperhomocysteinemia and the coagulation cascade
Thus, it can be perceived that elevated homocysteine levels will lead to prothrombotic state by enhancing the pro-coagulant pathway and/or suppressing the anticoagulant pathways.
Hyperhomocysteinemia and atherosclerosis
I) Homocysteine mediates cholesterol dysregulation
Homocysteine plays an important role in cholesterol biosynthesis by inducing the transcription as well as translation of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthesis (Figure 5, branch 1). It also increases cholesterol synthesis and accumulation in endothelial cells . Inhibitors of HMGCR like simvastatin prevented the homocysteine-induced accumulation of cholesterol. Thus, it can be perceived that elevated levels of homocysteine result in cholesterol biosynthesis dysregulation. Furthermore, as mentioned earlier, sterol regulatory element-binding protein-2 (SREBP), a transcription factor, is activated in the liver of hyperhomocysteinemic rats and the activation of SREBP-2 leads to hepatic lipid accumulation by regulating HMG-CoA reductase expression in the liver . Hyperhomocystenemia also modulates cholestrol biosynthesis pathway through upregulation of the ER chaperone, GRP78/BiP in hepatocytes while the actual transport of the cholesterol in endothelial cells was found to be downregulated leading to upregulation of HMGCR in endothelial cells .
Ii) Homocysteine affects LPL and Lox-1 expression, which leads to atherosclerosis
Homocysteine has been found to induce the expression of macrophage lipoprotein lipase (LPL) both at the transcription and translation level presumably via PKC activation [, figure 5, branch 6]. LPL is the major lipolytic enzyme involved in hydrolysis of triglycerides in lipoproteins . It is secreted by macrophages in atherosclerotic lesions and macrophage LPL produced in the vascular wall acts as a pro-atherogenic protein. This enzyme mediates the uptake of lipoproteins by macrophages, promotes lipoprotein retention to the extracellular matrix, induces the expression of the proatherogenic cytokine TNF-α, increase monocyte adhesion to endothelial cells and proliferation of vascular smooth muscle cells. It also promotes foam cell formation and atherosclerosis in vivo. Homocysteine was found to simultaneously change macrophage LPL & c-fos mRNA levels and induce the binding of nuclear protein to AP1 sequence (Figure 5, branch 7). This suggests that c-fos also may have a role to play in the stimulatory effect of homocysteine on macrophage LPL mRNA expression.
Homocysteine is known to down regulate the expression of peroxisome proliferators-activated receptors (PPARs) that are redox sensitive transcription factors in the vasculature belonging to the ligand-activated nuclear receptor family (Figure 5, branch 9). They play a key role in regulating expression of genes that control glucose and lipid metabolism and has been implicated in metabolic disorders leading to atherosclerosis. PPAR agonists like fibrates are known to promote anti-inflammatory effects presumably via the induction of antioxidant enzymes by PPARs. Homocysteine can potentially bind to PPARs and compete with the PPAR ligands like fibrates . In fact it has been reported that homocysteine binds to PPARs with a 10 fold higher affinity than fibrates , a class of lipid-modifying agents that have been widely used to substantially decrease plasma triglyceride levels. It also results in moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Thus, elevated levels of homocysteine might lead to hyperlipidemia by competing with the PPAR ligands like fibrates which are known to catabolise VLDL and triglycerides .
Oxidized low density lipoprotein (OxLDL) (Figure 5, branch 8) is one of the major factor that is responsible for endothelial dysfunction is as it induces expression of adhesion molecules, chemokines like MCP1 and impairs the endothelium-dependent vasorelaxation. LOX-1 is the principle receptor of OxLDL in vascular endothelial cells. Homocysteine has been reported to enhance endothelial LOX-1 gene expression and TNFα release upon oxLDL stimulation [[76, 77] Figure 5, branch 3]. Tontonoz et al demonstrated that oxLDL induces PPAR-γ in foam cell of atherosclerotic lesion, thus potentiating pathogenesis of atherosclerosis . Oxidized LDL has a role in the activation of PPAR-γ dependent gene expression and regulation of oxLDL receptor CD36. Thus, activation of PPAR-γ and CD36 constitute a positive feedback loop to potentiate the effects of oxLDL. PPARα and PPAR-γ can also suppress the inflammatory gene expression in monocytes, [79, 80] and mediate the anti-inflammatory response in the vessel wall. Hence, a balance between pro inflammatory effect of oxLDL and anti-inflammatory properties of PPARs determine the inflammatory status of cell/ vessel wall. Recent cross sectional studies report that oxidized LDL have higher association with angiographically documented coronary artery disease in patients 60 years or younger which implies that early onset CAD is more correlated with oxidized LDL thus by upregulating oxidized LDL receptors homocysteine induces athreosclerotic changes in an independent manner in both endothelial cells as well as mononuclear cells accelerating the rate of atherosclerosis .
(iii) Homocysteine modulates inflammatory gene response in endothelial cells
In endothelial cells, proinflammatory cytokines enhance the binding of NF-κB to DNA and cause up-regulation of NF-κB dependent genes [82, 83] (Figure 5, branch 6) Homocysteine has been reported to induce NF-κB activation in HUVECs and human aortic endothelial cells (HAECs). It also activates IκB-α resulting in nuclear translocation of NF-κB and enhanced NF-κB /DNA interaction. Thus, homocysteine cause an imbalance in intracellular signaling rather than a complete suppression of endothelial cell function. NF-κB may also play an important role in homocysteine-induced MCP-1 expression leading to monocyte macrophage accumulation in atherosclerotic lesions. Wang et. al  demonstrated that in homocysteine treated vascular smooth muscle cells both mRNA and protein levels of MCP-1 were increased through activation of PKC and superoxide production followed by NF-κB activation. MCP-1 & IL-8 are major chemokines for leukocyte trafficking and has been found in atheromatous plaques. The major route of action of MCP-1 is via its interaction with MCP-1 receptor on surface of monocyte (CCR2). Homocysteine stimulates CCR2 expression in monocyte leading to an enhanced binding and chemotactic response . Apart from MCP-1, homocysteine also up regulate the expression of IL-8 in cultured human monocyte via enhanced formation of homocysteine induced ROS (Reactive Oxygen species) . Homocysteine also induces expression of VEGF presumably via activation of NF-κB . VEGF has been found to be expressed in activated macrophages, endothelial cells, and smooth muscle cells in human coronary atherosclerotic lesions, but not in normal artery . VEGF has also been reported to increase atherosclerotic plaque size .
Moreover, in endothelial cells homocysteine modulates the expression of cell adhesion molecule-1 (sCAM-1)  which is generally perceived as a marker for vascular inflammation. Mansoor et. al. recently reported increase in the concentration of plasma homocysteine and triglycerides six hours after methionine and/or fat loading. It resulted in significant increase in the concentrations of P-selectin, E-selectin and VCAM-1 in healthy volunteers (Figure 5, branch 4).
Increasing evidence suggests the role of hyperhomocysteinemia in the underlying pathophysiological mechanism of the increased vascular risk development of coronary artery disease in patients with T2DM (Type 2 Diabetes Mellitus). The mechanisms by which homocysteine promotes this and exerts its detrimental effects may relate to induction of endothelial dysfunction and/or chronic inflammation (Figure 5, branches 4–6). T2DM stems from the failure of the body to respond normally to insulin, called "insulin resistance", ultimately leading to hyperglycemic condition. This common form of diabetes is often associated with obesity. Studies on experimental models have suggested that obesity also is a state of chronic inflammation. Over the years increasing evidence has accumulated indicating an ongoing cytokine-induced acute-phase response (low-grade inflammation) to be closely involved in the pathogenesis of T2DM and associated complications such as dyslipidemia and atherosclerosis. Observation that plasma concentrations of proinflammatory markers viz. C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-α (TNF-α) in the obese are elevated has confirmed the same. The interactions between the proinflammatory cytokines are shown in (figure 6). Association of hyperhomocysteinemia with elevated levels of proinflammatory cytokine in T2DM patients substantiates its role in accelerating diabetes associated atherosclerosis . Impaired SAM synthesis in liver tissue has also been shown to enhance production of pro-inflammatory cytokines and mediators .
V) Hypertension, angiotensin II and atherosclerosis
Hypertension is a risk factor for cardiovascular disease, and experimental evidence supports a role of renin-angiotensin system in contributing to pathogenesis of atherosclerosis [, Figure 5]. Untreated hypertension is associated with disturbed glutathione redox status and increased plasma homocysteine concentrations . Hypertension associated with the elevation of angiotensin II levels results in the induction of smooth muscle cell superoxide via NADPH oxidase [95, 96]. In addition, angiotensin II has also been shown to stimulate MCP-1 and VCAM -1 expression in rat aorta  and elevate LOX-1 expression in cultured vascular endothelial cells . Interestingly, homoctysteine as mentioned above induces the expression of MCP-1, VCAM-1 and LOX-1 [77, 85]. Thus, elevated levels of homocysteine may lead to hypertension by mechanisms similar to that of angiotensin II. This hypothesis is further supported by the report that methionine loading in normotensive and spontaneously hypertensive rats resulted in quantitative difference in homocysteine in the two rats. In spontaneously hypertensive rat, the serum levels of homocysteine were higher than in normotensive rats. Furthermore, methionine-related aortic alterations developed earlier were considerably more pronounced with the formation of additional connective tissue in spontaneously hypertensive rats . Interestingly, administration of angiotensin II exacerbated the methionine loading-related aortic alterations. Mild hyperhomocysteinemia is associated with stiffer small arteries with increased collagen deposition but these changes are accentuated by angiotensin II-induced blood pressure elevation . There is also a report, which suggests that in NIH/3T3 fibroblasts, angiotensin II induces GATA4 activity and homocysteine delayed this binding and hence alters the angiotensin II signaling . It is thus perceived that the deleterious effects of homocysteine may at least in part be mediated via modulation of angiotensin II -signaling for gene transcription.
vi) Homocysteine and extra cellular matrix
Homocysteine up regulates the synthesis and accumulation of SMC collagen [ Figure 5, branch 2] and several studies have demonstrated that homocysteine is mitogenic for arterial SMCs [103, 104] Extra-cellular matrix proteins like collagen are known to be critical components of atherosclerotic lesions . The proliferation of smooth muscle cells and synthesis of extracellular matrix are important determinants of the extent of lesion development and plaque stability. Fibrillar collagen has an important role in the pathogenesis of atherosclerosis due to its substantial contribution to the mass of connective tissue. It renders structural support for the plaques . Uncontrolled collagen accumulation leads to arterial stenosis, while excessive collagen breakdown combined with inadequate synthesis weakens plaques thereby making them prone to rupture.
Apart from collagen, homocysteine induces matrix metalloproteinases. Remodeling of extra-cellular matrix of the arterial wall by inducing elastolysis via activation of metalloproteinases in response to elevated levels of homocysteine is shown by studies in animal models. Chaussalet et al  showed that pathological levels of homocysteine increased the secretion of elastolytic metalloproteinase-2 and -9 and their activator kallikrein, in HUVECs . Furthermore, hyperhomocysteinemic patients had elevated mRNA levels of MMP-9 and tissue inhibitors of metalloproteinases-1 (TIMP-1) in freshly isolated peripheral blood mononuclear cells (PBMCs). Most importantly folic acid treatment reduced the levels of homocysteine and concomitantly a significant reduction in the levels of MMP-9 and TIMP-1 mRNA in PBMCs was observed .
Hyperhomocysteinemia: Neurological disorders
AD patients have elevated levels of homocysteine and decreased levels of SAM. This is believed to alter the DNA methylation status and hence gene expression in AD patients. This hypothesis is supported by the observation that SAM when added to human neuroblastoma SK-N-SH cells in culture, down-regulates expression of PS I gene coding for presenilin, a key factor for Aβ formation in AD due to methylation of its promoter . Similarly, there are other studies suggesting that levels of SAM, folate and vitamin B12 influence DNA methylation of the genes that are involved in the Aβ formation . Furthermore, it has also been reported that Herp, a homocysteine responsive protein, up regulated during ER stress, regulates PS-mediated amyloid beta generation presumably by binding to PS .
Homocysteine acts as an agonist and a partial antagonist at the glutamate binding site of the NMDA and the glycine-binding site of the receptor respectively. Under physiological conditions, when the concentration of glycine is normal, the neurotoxicity of homocysteine is observed at a very high concentration (millimolar range). However, under pathological conditions, such as in stroke or trauma where glycine levels in the brain is elevated, neurotoxicity of homocysteine is observed even at very low concentrations of homocysteine (10–100 μM) as the neurotoxic attributes of homocysteine exceeds its protective activity . Under physiological conditions excitation of glutamate receptors initiates the stimulation of lipases and phospholipases with the generation of second messengers that are necessary for normal cell function. However, over stimulation of glutamate receptors leads to excessive calcium entry, abnormal phosphorylation and proteolysis. Thus, increase in the concentration of homocysteine probably results in the over stimulation of glutamate receptors resulting in increased calcium influx. The neuronal damage is due to excess calcium influx and also the accumulation of reactive oxygen species.
Thus, we propose that homocysteine either by inducing oxidative stress or ER stress might lead to apoptosis which in turn may result in neurological disorders. Alternatively homocysteine might act on glutamate receptors triggering a cascade of events that might result in the disease.
Polymorphisms in genes resulting in hyperhomocysteinemia
Quantitative differences in the activity and availability of enzymes involved in regulation of homocysteine levels directly or indirectly are important in regulating the levels of homocysteine and hence phenotype of complex diseases. The factors that contribute to quantitative variation between individuals are repeat and single nucleotide polymorphism at the genetic level and epigenetic modifications. There are several attempts to analyze polymorphism in genes related to homocysteine pathway. A similar analysis of polymorphism in genes that are part of the interlinked network would be necessary to understand the implications of plasma homocysteine levels on predisposition and manifestation of complex diseases.
An exhaustive list of Gene polymorphism studies that have reported to affects the plasma level of homocysteine
Gene expression /Enzyme Activity
31 bp VNTR (exon 13-intron 13)
844Ins68 (Exon 8)
↑ (P) 
A 28-bp repeat (Enhancer region)
A 6-bp deletion (3'UTR)
↓ (del/del) 
Alteration in transcription level
CA Repeats (Intron 13)
↑ (In female) 
4G Ins/del (Promoter)
Affects the response of the PAI-1 promoter to cytokines 
Impairs APC mediated inactivation of factor Va 
Trascobalamin II (TCN II) facilitates the transport of the vitamin B12 to various tissues. Genetic variations in TCNII gene such as Pro259Arg significantly decrease holo- TCNII or holo-TCNII concentrations . Karin et al have mentioned that cardiovascular disease patients and normal controls, who have high vitamin B12 (>299 pmol/L), tHcy concentrations are lower in individuals homozygous for occurrence of proline259 (259PP) in TCNII protein compared to those with 259PR and 259RR. Therefore, 259PP individuals may be more susceptible to reduction of plasma tHcy in response to increase in vitamin B12 levels .
Polymorphism in genes is population dependent. Thus, it might be important to study the status of all these polymorphism in different cohorts to evaluate the importance of each of these polymorphisms with respect to hyperhomocysteinemia.
The challenges of understanding the molecular etiology of complex diseases is in designing a comprehensive analysis of genetic and epigenetic factors that contribute to quantitative differences in the levels of proteins coded by genes in pathways relevant the disease phenotype. The source of data to derive a rational list of genes for analysis is the literature where interactions and functional relationships between individual gene products have been elucidated. The present study is aimed at generating a resource for selection of genes for polymorphism screening and analysis of mutations as well as epigenetic modification in relation to hyperhomocysteinemia.
We have compiled a gene-list for researchers interested in deciphering the molecular basis of the role of homocysteine as an independent risk factor in cardiovascular diseases and other complex diseases. Among the variety of pathways that are modulated directly or indirectly by the levels of homocysteine, endoplasmic reticulum stress or ER stress emerges as a common pathway affecting different complex diseases. The data compiled here would assist the selection of genes for analysis based on the disease of interest and/or pathways of interest. Presently we are using the gene list for population specific frequency of known SNP and for discovery of new SNP.
It is noted that the levels of Homocysteine may be closely linked to epigenetic effects both as post-replication and post-translation modification. Methylation of histones plays an important role in chromatin remodeling and maintenance of the remodeled state through mitosis. With reference to post-replication modification of CpG sequences homocysteine pathway can function as a auto-regulatory process with reference to methylation of 5'upstream sequences of genes central to its own metabolism: while it can also influence the expression of other genes by regulation of levels of SAM for methylation of 5' upstream sequences. Thus a pathway related analysis of SNP as well as variation at epigenetic level is necessary for complete understanding of the molecular mechanisms relating homocysteine levels and complex disorders.
List of abbreviations
- B2 :
- B12 :
- 5f-THF :
- 5-CH3THF :
- dUMP :
Uridine -5-prime monophosphate
- dUTMP :
Tymidine -5-prime monophosphate
- DMG :
- DMGDH :
- M + :
- ERKP :
Phophorylation of Extracellular signal regulated kinase
- eIF-2α :
Eukaryote initiation factor 2 α
- CHOP :
- PERK :
PKR-like endoplasmic reticulum eIF2alpha kinase
- CEBPB :
CCAAT/enhancer -binding protein alpha
- EGR1 :
Early growth response 1
- CCND1 :
- IL6R :
Interleukin 6 receptor
- LEP :
- LEPR :
- PTX3 :
- STAT3 :
Signal Transducer And Activator Of Transcription 3
- TNFRSF1B :
Tumor Necrosis Factor Receptor Member 1A
- PLA2 :
- LOX :
- COX :
- PS :
- PARP :
The study was supported in part by funds provided by the Department of Biotechnology, Govt. of India (SS and VB) under project BT/PR4525/Med/14/533/2003. The authors are grateful to Dr. Dwaipayan Bharadwaj and Mythily Ganapathi for critically evaluating the manuscript. P S is grateful to the University Grant Commission and AM and AS to the Council of Scientific and Industrial Research (CSIR) for Junior Research Fellowship. SK is grateful to CSIR for his fellowship.
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