Homocysteine and Hypertension in Diabetes: Does PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>  Have a Regulatory Role?

Sen, Utpal; Tyagi, Suresh C.

doi:https://doi.org/10.1155/2010/806538

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Review Article | Open Access

Volume 2010 | Article ID 806538 | https://doi.org/10.1155/2010/806538

Homocysteine and Hypertension in Diabetes: Does PPARγ Have a Regulatory Role?

Utpal Sen¹and Suresh C. Tyagi¹

Academic Editor: Tianxin Yang

Received01 Sept 2009

Revised11 Nov 2009

Accepted10 May 2010

Published29 Jun 2010

Abstract

Dysfunction of macro- and microvessels is a major cause of morbidity and mortality in patients with cardio-renovascular diseases such as atherosclerosis, hypertension, and diabetes. Renal failure and impairment of renal function due to vasoconstriction of the glomerular arteriole in diabetic nephropathy leads to renal volume retention and increase in plasma homocysteine level. Homocysteine, which is a nonprotein amino acid, at elevated levels is an independent cardio-renovascular risk factor. Homocysteine induces oxidative injury of vascular endothelial cells, involved in matrix remodeling through modulation of the matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) axis, and increased formation and accumulation of extracellular matrix protein, such as collagen. In heart this leads to increased endothelial-myocyte uncoupling resulting in diastolic dysfunction and hypertension. In the kidney, increased matrix accumulation in the glomerulus causes glomerulosclerosis resulting in hypofiltration, increased renal volume retention, and hypertension. PPAR agonist reduces tissue homocysteine levels and is reported to ameliorate homocysteine-induced deleterious vascular effects in diabetes. This review, in light of current information, focuses on the beneficial effects of PPAR agonist in homocysteine-associated hypertension and vascular remodeling in diabetes.

1. Introduction

The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear receptor family of ligand-activated transcription factors that regulate gene expression [1, 2]. PPAR heterodimerizes with retinoid X receptor (RXR) and the ligand-activated PPAR binds to a specific DNA binding site, termed the PPAR response element (PPRE) [3, 4] to become transcriptionally active. There are three PPAR subtypes—PPAR, PPAR (also known as PPAR), and PPAR, which regulate gene expression in a variety of process, including lipid and glucose metabolism, atherosclerotic plaque formation, cellular differentiation, angiogenesis, inflammation, hypertension, and heart failure [5–7]. Although three subtypes of PPAR share many aspects of biology, each of the isoforms has specific tissue distribution, ligand selectivity, and unique biological effects [8]. PPAR is highly expressed in the liver, and mainly regulates lipid uptake and fatty acid catabolism. The vascular endothelial cells play a major role in regulating vascular tone, and although endothelial cells expresses PPAR [9], the role of PPAR and its agonist on blood pressure is still uncertain and controversial [7]. PPAR/ is the most widely expressed isoform that is expressed at low levels in almost all tissues. Studies in animal models have shown that although PPAR does not have role in changing blood pressure, it does have antiatherogenic effect [10]. PPAR is expressed at the highest levels in adipose tissue, where it regulates numerous genes and improves insulin sensitivity, increases fatty acid uptake, and decreases lipolysis. It was first described as an anti-inflammatory agent, however, the expression of PPAR in vascular endothelial cells and vascular smooth muscle cells raises the possibility of its involvement in the regulation of vascular tone and blood pressure [11].

Glitazones are a class of drugs primarily used to treat type 2 diabetes and related diseases. Glitazones bind to PPAR, specifically PPAR, and activate the receptor, which in turn increases the insulin sensitivity and are clinically used to control hyperglycemia in type 2 diabetes. It is known that 65% of diabetic patients also suffer from hypertension and treatment with glitazone was also noted to lower blood pressure. Diabetic subjects also often experience renal volume retention. This is one of the mechanisms by which diabetic subjects accumulate homocysteine in the body. Interestingly, clinical research suggests that at elevated levels, homocysteine is an independent risk factor for greater mortality in type 2 diabetic patients as compared to nondiabetic subjects [12]. In animal models of type 2 diabetes, glitazone (pioglitazone) is reported to reduce tissue (but not plasma) homocysteine level resulting in decreased cardiac remodeling, contractile dysfunction, and hypertension [13]. In this review, we discuss the beneficial effects of PPAR activation on vasculature through homocysteine clearance, which leads to improvement of endothelial-dependent vascular relaxation, in addition to its known hypoglycemic activity, resulting in restoration of blood pressure in diabetic nephropathy.

2. Renal Mechanism of Hypertension in Diabetes

In diabetes, progressive renal failure leads to end-stage renal disease [14]. Increased urinary albumin excretion, decline glomerular filtration rate (GFR) and high blood pressure are the hallmarks of diabetic nephropathy [15]. These renal functional changes during diabetes develop as a consequence of structural abnormalities and changes in podocytes. Impaired autoregulation of glomerular filtration rate (GFR) in diabetic kidney raises the blood pressure in the glomerular microcirculation [16]. Structural abnormalities including glomerular basement membrane thickening, mesangial expansion, extracellular matrix accumulation leads to glomerulosclerosis and interstitial fibrosis [17]. This raises blood pressure in the renal microcirculation and over time, uncontrolled high blood pressure can even further damage the blood vessels and nephrons causing renal volume retention and sodium accumulation in diabetes. These extra fluids and sodium linger in the bloodstream, putting extra pressure on the walls of the blood vessels, and raises the blood pressure.

3. Hypertension-Associated Renal Complications in Diabetes

Sustained elevation of blood pressure amplifies diabetic complications within the glomerulus by inducing impairment of autoregulation of the microcirculation, resulting in an increase in intraglomerular capillary pressure [17]. The changes of capillary pressure are paralleled by changes in overall glomerular volume [18, 19] and cyclic changes in glomerular volume lead to recurrent episodes of stretch and relaxation of all the glomerular component, including mesangial cells [19] and podocytes [20]. In vitro experimental evidences suggest that cyclic stretch/relaxation episodes in mesangial cells lead to production of extracellular components such as collagen [21], increases expression of profibrotic transforming growth factor-1 (TGF-1) [22], enhances the expression of the cytokine monocyte chemoattractant protein-1 (MCP-1) [23] and the cell adhesion molecule intercellular cell adhesion molecule-1 (ICAM-1) [24]. These molecules mediate and/or amplify renal damage [17]. In addition, accumulation of plasma homocysteine in diabetic nephropathy further contributes to renal damage and hypertension-associated renal complications [25, 26].

4. Renal Insufficiency, Homocysteine Accumulation, and Hypertension

Homocysteine is a nonprotein amino acid and metabolite of methionine. Homocysteine can be recycled into methionine; however, dysregulated methionine metabolism leads to accumulation of plasma homocysteine levels termed as hyperhomocysteinemia (HHcy). HHcy is an independent vascular risk factor and plasma homocysteine increases during renal insufficiency [27, 28]. There are four ways by which homocysteine can accumulate in the plasma. These are () a methionine-rich diet, such as meat, () deficiency of vitamin /folate, () deficiency of CBS activity (heterozygous or homozygous, CBS or CBS) and vitamin , and (4) renal insufficiency causing volume retention (Figure 1). Herein, we discuss how renal insufficiency and impaired glomerular filtration can cause accumulation of plasma homocysteine, which may contribute to hypertension.

Elevated level of plasma homocysteine has always been associated with patients exhibiting chronic kidney diseases, especially end-stage renal disease (ESRD) and the prevalence of HHcy is strongly associated with decreased glomerular filtration rate (GFR) [29]. Although the precise mechanism by which GFR is related to plasma homocysteine concentration is not well established, the association of plasma homocysteine and GFR has been shown to be linear [30, 31], with increase in plasma homocysteine level corresponding to a greater decline of GFR [32]. Thus, the association between hyperhomocysteinemia and renal failure may be causal where renal dysfunction increases plasma homocysteine level. There are two different hypotheses proposed for homocysteine accumulation during renal dysfunction [29]. These are () homocysteine clearance is disturbed in the failing kidney; () extrarenal homocysteine metabolism is impaired during renal failure. These are discussed below.

4.1. Homocysteine Metabolism and the Failing Kidney

The kidney is capable of filtering homocysteine, as it does for other amino acids. However, the amount of filtered homocysteine found in urine is minimal (6 mol/day, which is 1%), suggesting that most of the (99%) filtered homocysteine is reabsorbed by the kidney. The location of this uptake is reported to be on the basolateral tubule cell surface [33]. The kidney contains both transulfuration (cystathionine -synthase and cystathionase) and remethylation (methionine synthase) enzymes in human [29, 33] and rats [34], which indicate that theoretically both enzymatic pathways can be used. The in vitro and in vivo studies in rat however suggest that homocysteine is primarily metabolized by transulfuration pathway (Figure 1) to form cystathionine, which is further split into cysteine and -ketobutyrate [35, 36]. It is hypothesized that the kidney compensates the changes in GFR by up- or downregulating the biochemical pathways of homocysteine metabolism, thereby keeping the constant amount of homocysteine in the urine of normal healthy subjects [30]. As renal function declines during ESRD, plasma homocysteine level increases and the vast majority of dialysis patients experience mild-to-moderate hyperhomocysteinemia [37]. Studies have demonstrated inverse relationship between homocysteine and renal function [30, 33], and powerful indirect evidence suggests that elevated plasma homocysteine levels in renal disease are intimately associated with kidney function [33].

4.2. Renal Failure and Extrarenal Homocysteine Metabolism

Studies using a stable isotope method of whole body sulphur amino acid metabolism in ESRD patients and healthy subjects conducted by the research group led by van Guldener et al. [38–40], report that total remethylation and transmethylation flux were decreased in ESRD patients without any change in transulfuration rate as compared to control subjects. Based on their findings, they suggested two possible mechanisms that could explain elevated plasma homocysteine level in ESRD. These are () a defect in the sulfur amino acid metabolism that would lead to accumulation of homocysteine, and/or () a defect in homocysteine remethylation, which eventually increases the level of homocysteine. In any or both the cases homocysteine will be accumulated in the body due to impaired metabolism

5. Homocysteine and Hypertension

The concerns are “is hyperhomocysteinemia associated with hypertension; if so, is this relationship causal; and if that is the case, does PPAR activation prevent this change?” At present, it does not appear that there is sufficient affirmative literature on these topics. However, the hypothesis that homocysteine may play a role in the pathogenesis of essential hypertension is based on the fact that homocysteine induces arteriolar constriction, renal dysfunction and increased sodium reabsorption, and increases arterial stiffness [41, 42]. Also, elevated homocysteine is known to increase oxidative stress that causes oxidative injury to the vascular endothelium, diminishes vasodilation by nitric oxide, stimulates the proliferation of vascular smooth muscle cells, and alters the elastic properties of the vascular wall [43]. All these are associated with the rise in hypertension. Thus, homocysteine may contribute to blood pressure elevation.

6. Diabetic Nephropathy and Homocysteine Clearance: The Role of PPAR

Diabetes mellitus, a chronic metabolic disorder, is associated with increased risk of cardio-renovascular diseases such as arterial disease, stroke, and nephropathy [44, 45]. Diabetic nephropathy (DN) is a leading cause of morbidity and mortality in hyperglycemic patients and the most common single condition found in end-stage renal disease (ESRD) [46]. The majority of diabetic patients with renal failure suffer from glomerulopathy which is characterized by glomerulosclerosis, increased thickness of the glomerular basement membrane, glomerular hypertrophy, mesangial cell expansion, podocytic loss, and tubulointerstitial fibrosis leading to progressive reduction of glomerular filtration rate (GFR) [46, 47]. Chronic diabetes reduces PPAR mRNA level in the glomeruli [48] and in the pathogenesis of DN downregulated PPAR expression is associated with matrix accumulation, such as collagen IV and glomerulonephritis [49–52]. Activation of PPAR regulates gene expressions that promote insulin sensitization and glucose metabolism [53]. In addition, several studies have demonstrated the efficacy of PPAR agonists to inhibit the progression of glomerulosclerosis [54] and have suggested that PPAR ligands have a direct beneficial renal effect. For example, in experiments on diabetic rats with nephropathy, treatment with PPAR agonist reduced the occurrence of albuminuria and prevented the development of glomerulosclerosis and glomerular hypertrophy (Figure 2) by suppressing TGF-, VEGF, PAI-1, collagen IV, and ICAM-1 [55, 56]. We have reported that PPAR agonist ciglitazone improved GFR and glomerular architecture in diabetic nephropathy, in part, by normalizing tissue levels of homocysteine in the glomerulus [25]. Impairment of renal function, as evidenced by reduced GFR was noticed due to vasoconstriction of glomerular arteriole (Figure 3), which resulted renal volume retention and increased plasma homocysteine levels [57]. Elevated plasma homocysteine, in turn, caused chronic and impaired renal filtration and was also reported as a risk factor for diabetic nephropathy [58, 59]. Activation of PPAR induced insulin sensitivity in type 2 diabetes and promoted tissue uptake of homocysteine; these resulted in lowering of plasma homocysteine levels [57, 60]. Contrary to this mechanism in type 1 diabetes the plasma homocysteine level did not change, although increased glomerular tissue level of homocysteine became normal with CZ treatment [25]. We suggested that this change of tissue homocysteine level was probably because of improvement of diabetic nephropathy that normalized renal volume retention and accelerated the clearance of glomerular tissue homocysteine. This finding was in accordance with the clinical trials where PPAR agonists ameliorated endothelial dysfunction in hyperhomocysteinemia (HHcy) with no effect on plasma homocysteine level [61].

Figure 2

Glomerular hypertrophy and collapse in diabetes were ameliorated by ciglitazone. Histological kidney section were stained with Masson-Trichrome stain and visualized under dissecting microscope. Note that glomerular hypertrophy was observed at one week of alloxan (a single dose of 65 mg/kg body wt intraperitoneally) treatment. At 10 weeks glomerulus was collapsed. Ciglitazone treatment after 10 weeks of alloxan treatment reversed glomerular deformation towards normal (magnification, x200).

(a)

(b)

(c)

(d)

Figure 3

Increased media-lumen ratio of preglomerular arteriole and tubule of diabetic mice were normalized with ciglitazone treatment. Kidney sections of 0 wk (a), 10 wk of alloxan treatment (b), and 10 wk of alloxan treatment followed by another 6 wk of CZ treatment (c) were stained with Masson-Trichrome. (d) Preglomerular arterioles of these stained sections were identified under a microscope, and medial/lumen ratio was calculated by a digital micrometer and plotted (

data presented \pm SE,

n = 6

animals/group;

{}^{*}P < . 01

compared with 0 wk;

{}^{* *}P < . 05

compared with 10 wk). The results indicated that medial/lumen ratio was increased dramatically due to thickening of the media and narrowing of the lumen after 10 wk of alloxan treatment. Interestingly, ciglitazone treatment almost normalized the media/lumen ratio indicating the involvement of PPAR

γ

in this process.

7. Homocysteine, Matrix Remodeling, and Hypertension: The Role of PPAR

Extracellular matrix (ECM) plays an important role in maintenance of tissue architecture and normal physiological function. Remodeling of extracellular matrix (ECM) is a dynamic process and excessive ECM deposition is a pathophysiological phenomenon of diseased condition that could lead to hypertension [62–64]. A number of enzymes engage in the regulation of ECM turnover. Among these are MMPs and their natural inhibitor, TIMPs. MMPs are members of a family of - and -dependent endopeptidases, which are essential for tissue remodeling in both physiologic and pathophysiologic conditions. MMP enzymes in the normal physiologic condition reside in the latent form and are activated by various physiological threats [60]. Among MMPs, MMP-2, and MMP-9 are gelatinases that degrade collagen IV and are essential in maintaining the integrity of the glomerular basement membrane. Because the turnover of collagen is faster that gelatin, oxidatively modified collagen deposits in the tissue causing fibrosis. In diabetic nephropathy activities of MMPs and TIMPs mostly regulate ECM degradation [65]. Type IV collagenases, MMP-2 and -9, have been studied extensively in various glomerular diseases with conflicting results [57, 65–67]. We have shown previously that increases in glomerular homocysteine and activation of MMP-2 are associated with glomerulosclerosis [57]. It was, however, unclear how MMPs and TIMPs are involved in glomerulosclerosis and whether PPAR, in part, regulates these enzymes that modulate glomerular dysfunction in DN. Recently, we reported that both MMP-2 and -9 activities were increased significantly in diabetic kidney [25], and this result was in accordance with the similar findings reported by independent laboratories, including our own [57, 63, 68, 69]. We also showed that expression of TIMP-1 was upregulated in the glomeruli of diabetic mice [25], which was in agreement with the previously reported study by Eddy et al. [70] where progressive renal fibrosis was characterized by upregulation of TIMP-1 expression. At the onset of diabetes, the kidney grows larger, but it eventually shrinks with reduced GFR, proceeding to sclerosis and renal failure. We have reported that subnormal GFR was noticed at the latter stage of alloxan-induced diabetes in mice, and increase in renovalcular resistance was accompanied by collapse of preglomerular arteriole and the glomerulus [25]. This was in part due to MMP/TIMP imbalance and the accumulation of ECM matrix. PPAR agonist CZ treatment normalized these matrix proteins in diabetic kidney through activating PPAR and homocysteine clearance; thus, resulted in restoration of renal architecture, normal glomerular function, and vascular resistance of the renal arteriole [25]. A proposed mechanism of homocysteine associated matrix accumulation and hypertension has been depicted in Figure 4.

Figure 4

Proposed mechanism of homocysteine associated hypertension in diabetes. Diabetes causes renal microvascular constriction and deposition of extracellular matrix in the glomerular basement membrane. This causes glomerulosclerosis and impaired glomerular function (GFR). Renal hypofiltration increases plasma homocysteine level, which further cause oxidative stress and amplifies glomerular injury. Increased matrix accumulation in the myocardium leads to deposition of extracellular matrix between endothelium and myocyte causing endothelium myocyte uncoupling. This causes prevention of NO to pass through the matrix barrier and impairs left ventricular diastolic dysfunction. Glomerulosclerosis and L-V diastolic dysfunction results in hypertension.

8. Homocysteine Handling in the Heart: The Role of PPAR

Until recently, it was our main concern to control systolic blood pressure and to keep this pressure as close as possible to normal level to minimize hypertension-associated morbidity and mortality. Recent studies however, have shifted our attention to diastolic hypertension which can be as harmful as systolic hypertension. A constant elevated diastolic pressure increases the risk of heart damage, brain damage, and kidney problems as well. One of the causes of diastolic hypertension is diastolic dysfunction, which demonstrates hypertrophy of the cardiomyocytes, increased interstitial collagen deposition and/or infiltration of the myocardium leading to endothelial-myocyte uncoupling. It is estimated that, although the majority of cardiac muscle is myocyte, sixteen percent of the myocardial mass is capillaries and the inner lining of the capillaries are made up endothelium [71]. The capillary endothelium is embedded in the cardiac muscle, and plays an important role in myocardial diastolic relaxation, in addition to those which myocytes contribute. Nitric oxide (NO) from the endocardial endothelium alters the contractile and relaxant properties of the heart [72]. A gradient of NO concentration, that is, high in endocardium and low in mid myocardium, has been documented [72], which suggests that there is more capillary endothelium in the endocardium than in epi- or mid-myocardium. Since capillary endothelial cells are embedded in the muscle, the contribution of endothelium to cardiac relaxation is the least studied. We have studied LV tissue function using a cardiac ring preparation in a tissue myobath and assessed the effects of hyperhomocysteinemia on myocardial endothelium-dependent relaxation [73]. In alloxan-induced diabetic mouse heart, our study demonstrated both plasma and myocardial tissue level of homocysteine increased. However, the tissue level of homocysteine was reduced by PPAR agonist (CZ)-treated diabetic mice without any alteration of plasma homocysteine level [73]. The decreased myocardial tissue level of homocysteine in diabetic heart treated with PPAR agonist was found to improve myocardial relaxation in vitro in both an endothelium dependent and independent way [73]. Endothelium dependent cardiac relaxation was measured by acetylcholine and bradykinin, where acetylcholine works through the endothelium-dependent NO generation, and bradykinin works on blood vessels through nitric oxide and endothelial-derived hyperpolarizing factor. Both factors have shown that endothelium dependent relaxation was impaired in diabetic cardiac rings [73]. Interestingly, endothelium independent vascular relaxation induced by sodium nitropruside also reduced cardiac relaxation in vitro in cardiac rings prepared from diabetic heart. This suggests that traveling of NO to the capillary smooth muscle cells was somehow impaired. This we referred to as endothelial-myocyte uncoupling, which did not allow nitropruside-generated NO to travel through the disrupted matrix between endothelium and myocyte. Thus, we have observed attenuated relaxation. However, treatment of diabetic mice with PPAR agonist CZ, normalized the relaxation of cardiac rings, suggesting the attributed role of CZ in endothelial-myocyte recoupling in diabetes [73]. This study demonstrated that tissue levels of homocysteine contributed endocardial endothelium function and PPAR activation promoted tissue clearance of homocysteine thereby improving endothelium dependent cardiac relaxation. On the other hand endothelium independent relaxation was improved in part by recoupling of endothelium and myocyte [73]. A possible mechanism of endothelium-myocyte uncoupling and hypertension in diabetes-associated hyperhomocysteinemic condition has been depicted in Figure 4.

9. Homocysteine, Protein Modification, and Hypertension: The Role of PPAR

Although the homocysteine is linked to blood pressure, a direct cause and effect relationship of hyperhomocysteinemia and hypertension has not been established. The mechanisms that could explain this relationship include homocysteine-induced arteriolar constriction, renal dysfunction, increased sodium absorption, increased arterial stiffness, and endothelial damage [74]. Other possible mechanisms that may be involved are () formation of homocysteine thiolactone and () protein homocysteinylation. At elevated levels homocysteine converts to homocysteine-thiolactone as a result of an error-editing function of some aminoacyl-tRNA synthetases, and the detailed mechanisms are described elsewhere [75–77]. Homocysteine-thiolactone is a reactive metabolite that causes protein N-homocysteinylation through the formation of amide bonds with protein lysine residues [77], which alters or impairs the protein’s function [76]. -linked protein Hcy (N-Hcy-protein) has been reported to be elevated in hyperhomocysteinemia [78–81], and has been documented to accumulate in atherosclerotic lesions in mice [82]. Protein homocysteinylation damages protein, manifests multimerization, and precipitates extensively modified proteins [76], which can cause cardiovascular diseases. For example, CBS-deficient patients have significantly high levels of plasma prothrombotic N-Hcy-fibrinogen [81], which leads to abnormal resistance of fibrin clots to lyses and contributes to increased risk of thrombosis. Thus, although presently the hypothesis that elevated homocysteine causes hypertension still remains unproven, the contributing role of hyperhomocysteinemia in the renovascular diseases, such as diabetic nephropathy to elevate blood pressure can not be ignored as substantial indirect evidence linked to hypertension during these disease processes.

Genetic variations have been demonstrated to play an important role in determining plasma homocysteine levels. For example, sequence variation of methylenetetrahydrofolate reductase (MTHFR) gene has been shown to influence circulating homocysteine level [83], and sequence variation of amino acid 222 from alanine to valine (p.A222V) has been reported to elevate circulating concentrations of homocysteine [84]. The PPAR produces a number of isoforms which control a variety of pathways including lipid metabolism, insulin sensitivity, and inflammation [85]. Therefore, these transcription factors may play a significant role in controlling the enzymes critical for homocysteine production or metabolism. Interestingly, studies in animal models and patients have shown PPAR ligation to reduce circulating homocysteine concentration [86, 87]. Thus, the findings that the pharmacological PPAR ligands are able to reduce circulating homocysteine concentrations fit well with a role of PPAR in modulating homocysteine turnover [86, 87]. We have demonstrated that activation of PPAR in diabetic subjects reduced tissue homocysteine level and normalized systolic blood pressure [73]. Thus, it may be possible that PPAR activation reduces hypertension through reduction of homocysteine, at least in part. However, as direct link of hyperhomocysteinemia and hypertension is still not established, the issue of whether or not the reduction of homocysteine level through PPAR activation reduces blood pressure remains debatable and controversial. Future studies are needed to establish a direct cause and effect relationship between hyperhomocysteinemia and hypertension, if any. Nonetheless, it is time to speculate that hyperhomocysteinemia contributes to elevate blood pressure in the pathogenesis of renal disease, for example, diabetic nephropathy, and PPAR is an effective target molecule to regulate hypertension, at least in part, through the reduction of homocysteine, where renal insufficiency upregulates homocysteine.

10. Hydrogen Sulfide, Inflammation, and Hypertension: The Role of Homocysteine

Hydrogen sulfide (S) has been known for the decades as a noxious gaseous molecule with an intoxicating effect on the brain and central nervous system. Recent findings, however, reported that it is an effective molecule to regulate blood pressure [88, 89]. Endogenously, S is generated in the mammalian tissue from L-cysteine, and homocysteine is the precursor of L-cysteine. Physiologically, homocysteine is metabolized by three transulfuration pathway enzymes, cystathionine -synthase (CBS), cystathionine -lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). At elevated levels, homocysteine has been shown to reduce activity of CSE, thereby reducing the production of S [90]. Studies from independent laboratories reported that, at low levels, S defends organs from several pathophysiological conditions, such as oxidative stress, ischemia-reperfusion, and hypertension [88, 91, 92]. Interestingly, results from in vitro studies suggest that at low levels S decreases hydrogen peroxide (), peroxynitrite (), and superoxide anion () generation induced by homocysteine in a cell culture model [93].

It is known that rise in blood pressure causes chronic inflammation of the endothelium which is, in turn, responsible for further endothelial damage and worsening blood pressure. On the other hand, several metabolic disorders such as dyslipidemia, hyperhomocysteinemia, diabetes, and obesity cause inflammation followed by a subsequent rise of blood pressure. Inflammatory disease such as atherosclerosis is a major complication of hypertension [94], and plays a critical role in hypertensive renal disease, whereas treatment of renal inflammation by melatonin has been shown to ameliorate hypertension [95]. Several studies have documented that homocysteine may directly or indirectly promote synthesis of several proinflammatory cytokines in the arterial wall and in the circulating cells. In particular, the expression of MCP-1 has been shown to increase in cultured human endothelial cell [96], smooth muscle cells [97], and in monocytes treated with homocysteine [98–100]. Additionally, homocysteine-thiolactone has recently been demonstrated to be more toxic than homocysteine, and possesses stronger proinflammatory properties [101]. Furthermore, homocysteine-thiolactone impairs insulin signaling, and thereby inhibits insulin-mediated glycogen synthesis [102]. We have reported that although PPAR activation did not have any effect on plasma homocysteine level, it promoted clearance of tissue homocysteine, in addition to its known action of increasing insulin sensitivity. Thus, the activation of PPAR in diabetic nephropathy modulates inflammatory reaction, at least in three different mechanisms: () increases insulin sensitivity and reduces plasma glucose level, therefore reduces inflammation; () promotes tissue clearance of homocysteine level and thus, reduces oxidative stress and inflammation; () normalizes CSE enzymatic activity, thereby raises the possibility of endogenous S generation, which has been documented as an anti-inflammatory and antihypertensive gaseous molecule at physiological levels [88, 103]. The possible pathways of these mechanisms are shown in Figure 5.

Figure 5

Schematic of PPAR

γ

-mediated reduction in inflammatory reaction and hypertension in diabetic nephropathy. Diabetes causes increase in homocysteine level and subsequent inhibition of hydrogen sulfide production in the body through the inhibition of cystathionine

γ

-lyase (CSE), an enzyme required for homocysteine metabolism. This leads to oxidative stress and causes hypertension. Homocysteine and diabetes induce chronic inflammation, which lead to atherosclerosis and hypertension. PPAR

γ

induction clears tissue homocysteine, in addition to regulating hyperglycemia, thereby reduces oxidative stress and hypertension.

11. Recent Clinical Trials and the Homocysteine Paradox

It is well established through decades with many large prospective studies that hyperhomocysteinemia predicts increased risk of vascular events including stroke, venous thromboembolism, and death [104, 105]. Many interventional trials paradoxically, however, failed to demonstrate any clinical benefit from homocysteine-lowering therapy [106–110]. The possible reasons are explained elsewhere [111]. Briefly, hyperhomocysteinemia is a clinically important risk factor at extremely high levels. All of the recent clinical trials of homocysteine-lowering therapy have been performed in subjects with relatively mild hyperhomocysteinemia [111]. The negative outcome of these trails may indicate that mild hyperhomocysteinemia is not a causative risk factor rather it is a marker of other vascular diseases and is associated with increased vascular risk. It is also possible that homocysteine lowering therapy may produce some adverse effect that mask the clinical benefit of lower homocysteine [108]. Also, the trials were conducted after the implementation of policies that mandate the addition of folic acid to white flour, cereals, and related products in the United States. This resulted in lower homocysteine concentration among US populations [112, 113]. Moreover, in none of the trials measurement of tissue homocysteine levels was considered. Although folic acid treatment lowered plasma homocysteine levels, it may have promoted tissue uptake of homocysteine, a similar effect where insulin reduced plasma homocysteine, but increased tissue homocysteine level [60]. This increased tissue homocysteine level mimicked the clinical benefit of homocysteine lowering effect of folic acid on cardiovascular events. Interestingly, a recent report suggests that in type 2 diabetic patients, metformin reduces both folate and vitamin B12, and increases homocysteine. Conversely, rosiglitazone decreases homocysteine level in the same time period. The clinical significance of these observations is not clear and remains to be investigated [87]. Some larger trials with longer homocysteine-lowering therapy are ongoing and we should wait until the outcomes of these trials finally settle the debate. Nevertheless, the kidney plays a major role in homocysteine metabolism and plasma homocysteine increases as renal function declines.

12. Concluding Remarks and Perspectives

Diabetes is the most common single factor of cardiovascular and renal damage in patients with diabetes mellitus. Diabetes causes tissue accumulation of homocysteine both in cardiac and glomerular tissue. This increased tissue content of homocysteine exacerbates cardiovasculopathy and nephropathy in diabetes, in addition to the detrimental effect of diabetes. PPAR agonists may be beneficial in preventing vasculopathies in cardiac and renal tissues associated with increased homocysteine content in diabetic subjects. Moreover, PPAR ligand seems to be promising in preventing hypertension associated with increased homocysteine level in diabetes. Although at present it is premature to conclude homocysteine causes hypertension, there is substantial indirect evidence which supports homocysteine-associated rise in blood pressure. Further studies are needed to elucidate the contributing role of homocysteine to regulate blood pressure, and precise mechanism of hypertension modulation associated with hyperhomocysteinemia by PPAR induction warrants special attention.

Abbreviations

CBS:	Cystathionine--synthase
CSE:	Cystathionine--lyase
CZ:	Ciglitazone
DN:	Diabetic nephropathy
ECM:	Extracellular matrix
ESRD:	End-stage renal disease
GFR:	Glomerular filtration rate
Hcy:	Homocysteine
HHcy:	Hyperhomocysteinemia
S:	Hydrogen sulfide
O₂:	Hydrogen peroxide
ICAM-1:	Intercellular cell adhesion molecule-1
LV:	Left ventricle
MIP-2:	Macrophage inflammatory protein 2
MMP:	Matrix metalloproteinase
NO:	Nitric oxide
:	Superoxide
:	Peroxynitrite
PAI:	Plasminogen activator inhibitor
PPAR:	Peroxisome proliferator-activated receptor
PPRE:	PPAR response element
RXR:	Retinoid X receptor
TGF-:	Transforming growth factor-
TIMP:	Tissue inhibitor of metalloproteinase
VEGF:	Vascular endothelial growth factor.

Acknowledgment

This research was supported, in part, by the National Institutes of Health grants, HL-74185, HL-71010, HL-88012, and NS-51568.

References

L. Michalik and W. Wahli, “Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions,” Current Opinion in Biotechnology, vol. 10, no. 6, pp. 564–570, 1999.
View at: Publisher Site | Google Scholar
S. Lee, W. Kim, S.-O. Moon et al., “Rosiglitazone ameliorates cisplatin-induced renal injury in mice,” Nephrology Dialysis Transplantation, vol. 21, no. 8, pp. 2096–2105, 2006.
View at: Publisher Site | Google Scholar
L. Michalik, J. Auwerx, J. P. Berger et al., “International union of pharmacology. LXI. Peroxisome proliferator-activated receptors,” Pharmacological Reviews, vol. 58, no. 4, pp. 726–741, 2006.
View at: Publisher Site | Google Scholar
T. Matsumoto, T. Kobayashi, and K. Kamata, “Relationships among ET-1, PPARγ, oxidative stress and endothelial dysfunction in diabetic animals,” Journal of Smooth Muscle Research, vol. 44, no. 2, pp. 41–55, 2008.
View at: Publisher Site | Google Scholar
A. Towfighi and B. Ovbiagele, “Partial peroxisome proliferator-activated receptor agonist angiotensin receptor blockers: potential multipronged strategy in stroke prevention,” Cerebrovascular Diseases, vol. 26, no. 2, pp. 106–112, 2008.
View at: Publisher Site | Google Scholar
J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002.
View at: Publisher Site | Google Scholar
R. Chen, F. Liang, J. Moriya et al., “Peroxisome proliferator-activated receptors (PPARs) and their agonists for hypertension and heart failure: are the reagents beneficial or harmful?” International Journal of Cardiology, vol. 130, no. 2, pp. 131–139, 2008.
View at: Publisher Site | Google Scholar
X. Ruan, F. Zheng, and Y. Guan, “PPARs and the kidney in metabolic syndrome,” American Journal of Physiology, vol. 294, no. 5, pp. F1032–F1047, 2008.
View at: Publisher Site | Google Scholar
N. Marx, G. K. Sukhova, T. Collins, P. Libby, and J. Plutzky, “PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells,” Circulation, vol. 99, no. 24, pp. 3125–3131, 1999.
View at: Google Scholar
Y. Takata, J. Liu, F. Yin et al., “PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 11, pp. 4277–4282, 2008.
View at: Publisher Site | Google Scholar
S. Z. Duan, M. G. Usher, and R. M. Mortensen, “PPARs: the vasculature, inflammation and hypertension,” Current Opinion in Nephrology and Hypertension, vol. 18, no. 2, pp. 128–133, 2009.
View at: Publisher Site | Google Scholar
E. K. Hoogeveen, P. J. Kostense, C. Jakobs et al., “Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn study,” Circulation, vol. 101, no. 13, pp. 1506–1511, 2000.
View at: Google Scholar
W. E. Rodriguez, I. G. Joshua, J. C. Falcone, and S. C. Tyagi, “Pioglitazone prevents cardiac remodeling in high-fat, high-calorie-induced type 2 diabetes mellitus,” American Journal of Physiology, vol. 291, no. 1, pp. H81–H87, 2006.
View at: Publisher Site | Google Scholar
N. R. Burrows, Y. Li, and L. S. Geiss, “Incidence of treatment for end-stage renal disease among individuals with diabetes in the U.S. continues to decline,” Diabetes Care, vol. 33, no. 1, pp. 73–77, 2010.
View at: Publisher Site | Google Scholar
T. Zelmanovitz, F. Gerchman, A. P. Balthazar, F. C. Thomazelli, J. D. Matos, and L. H. Canani, “Diabetic nephropathy,” Diabetology & Metabolic Syndrome, vol. 1, no. 1, p. 10, 2009.
View at: Google Scholar
P. K. Christensen, H. P. Hansen, and H.-H. Parving, “Impaired autoregulation of GFR in hypertensive non-insulin dependent diabetic patients,” Kidney International, vol. 52, no. 5, pp. 1369–1374, 1997.
View at: Google Scholar
S. Giunti, D. Barit, and M. E. Cooper, “Mechanisms of diabetic nephropathy: role of hypertension,” Hypertension, vol. 48, no. 4, pp. 519–526, 2006.
View at: Publisher Site | Google Scholar
P. Cortes, X. Zhao, B. L. Riser, and R. G. Narins, “Regulation of glomerular volume in normal and partially nephrectomized rats,” American Journal of Physiology, vol. 270, no. 2, pp. F356–F370, 1996.
View at: Google Scholar
P. Cortes, B. L. Riser, J. Yee, and R. G. Narins, “Mechanical strain of glomerular mesangial cells in the pathogenesis of glomerulosclerosis: clinical implications,” Nephrology Dialysis Transplantation, vol. 14, no. 6, pp. 1351–1354, 1999.
View at: Publisher Site | Google Scholar
N. Endlich and K. Endlich, “Stretch, tension and adhesion—adaptive mechanisms of the actin cytoskeleton in podocytes,” European Journal of Cell Biology, vol. 85, no. 3-4, pp. 229–234, 2006.
View at: Publisher Site | Google Scholar
T. Yasuda, S. Kondo, T. Homma, and R. C. Harris, “Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells,” Journal of Clinical Investigation, vol. 98, no. 9, pp. 1991–2000, 1996.
View at: Google Scholar
B. L. Riser, P. Cortes, C. Heilig et al., “Cyclic stretching force selectively up-regulates transforming growth factor-β isoforms in cultured rat mesangial cells,” American Journal of Pathology, vol. 148, no. 6, pp. 1915–1923, 1996.
View at: Google Scholar
G. Gruden, G. Setti, A. Hayward et al., “Mechanical stretch induces monocyte chemoattractant activity via an NF-κB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone,” Journal of the American Society of Nephrology, vol. 16, no. 3, pp. 688–696, 2005.
View at: Publisher Site | Google Scholar
B. L. Riser, J. Varani, P. Cortes, J. Yee, M. Dame, and A. K. Sharba, “Cyclic stretching of mesangial cells up-regulates intercellular adhesion molecule-1 and leukocyte adherence: a possible new mechanism for glomerulosclerosis,” American Journal of Pathology, vol. 158, no. 1, pp. 11–17, 2001.
View at: Google Scholar
U. Sen, W. E. Rodriguez, N. Tyagi, M. Kumar, S. Kundu, and S. C. Tyagi, “Ciglitazone, a PPARγ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance,” American Journal of Physiology, vol. 295, no. 5, pp. E1205–E1212, 2008.
View at: Publisher Site | Google Scholar
S. S. Soedamah-Muthu, N. Chaturvedi, T. Teerlink, B. Idzior-Walus, J. H. Fuller, and C. D. A. Stehouwer, “Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study,” Journal of Internal Medicine, vol. 258, no. 5, pp. 450–459, 2005.
View at: Publisher Site | Google Scholar
L. M. Graham, L. E. Daly, H. M. Refsum et al., “Plasma homocysteine as a risk factor for vascular disease: the European concerted action project,” Journal of the American Medical Association, vol. 277, no. 22, pp. 1775–1781, 1997.
View at: Google Scholar
J. Sundström, L. Sullivan, R. B. D'Agostino et al., “Plasma homocysteine, hypertension incidence, and blood pressure tracking: the framingham heart study,” Hypertension, vol. 42, no. 6, pp. 1100–1105, 2003.
View at: Publisher Site | Google Scholar
C. van Guldener, “Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering?” Nephrology Dialysis Transplantation, vol. 21, no. 5, pp. 1161–1166, 2006.
View at: Publisher Site | Google Scholar
F. Wollesen, L. Brattström, H. Refsum, P. M. Ueland, L. Berglund, and C. Berne, “Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus,” Kidney International, vol. 55, no. 3, pp. 1028–1035, 1999.
View at: Publisher Site | Google Scholar
B. A. J. Veldman, G. Vervoort, H. Blom, and P. Smits, “Reduced plasma total homocysteine concentrations in type 1 diabetes mellitus is determined by increased renal clearance,” Diabetic Medicine, vol. 22, no. 3, pp. 301–305, 2005.
View at: Publisher Site | Google Scholar
T. Ninomiya, Y. Kiyohara, M. Kubo et al., “Hyperhomocysteinemia and the development of chronic kidney disease in a general population: the Hisayama study,” American Journal of Kidney Diseases, vol. 44, no. 3, pp. 437–445, 2004.
View at: Publisher Site | Google Scholar
A. N. Friedman, A. G. Bostom, J. Selhub, A. S. Levey, and I. H. Rosenberg, “The kidney and homocysteine metabolism,” Journal of the American Society of Nephrology, vol. 12, no. 10, pp. 2181–2189, 2001.
View at: Google Scholar
J. D. Finkelstein, “Methionine metabolism in mammals,” Journal of Nutritional Biochemistry, vol. 1, no. 5, pp. 228–237, 1990.
View at: Publisher Site | Google Scholar
J. D. House, M. E. Brosnan, and J. T. Brosnan, “Renal uptake and excretion of homocysteine in rats with acute hyperhomocysteinemia,” Kidney International, vol. 54, no. 5, pp. 1601–1607, 1998.
View at: Publisher Site | Google Scholar
J. D. House, M. E. Brosnan, and J. T. Brosnan, “Characterization of homocysteine metabolism in the rat kidney,” Biochemical Journal, vol. 328, no. 1, pp. 287–292, 1997.
View at: Google Scholar
R. N. Foley, P. S. Parfrey, and M. J. Sarnak, “Clinical epidemiology of cardiovascular disease in chronic renal disease,” American Journal of Kidney Diseases, vol. 32, no. 5, pp. S112–S119, 1998.
View at: Google Scholar
C. van Guldener, W. Kulik, R. Berger et al., “Homocysteine and methionine metabolism in ESRD: a stable isotope study,” Kidney International, vol. 56, no. 3, pp. 1064–1071, 1999.
View at: Publisher Site | Google Scholar
F. Stam, C. van Guldener, P. M. ter Wee et al., “Homocysteine clearance and methylation flux rates in health and end-stage renal disease: association with S-adenosylhomocysteine,” American Journal of Physiology, vol. 287, no. 2, pp. F215–F223, 2004.
View at: Publisher Site | Google Scholar
F. Stam, C. van Guldener, P. M. Ter Wee, C. Jakobs, K. de Meer, and C. D. A. Stehouwer, “Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease,” Kidney International, vol. 67, no. 1, pp. 259–264, 2005.
View at: Publisher Site | Google Scholar
E. G. J. Vermeulen, H. W. M. Niessen, M. Bogels, C. D. A. Stehouwer, J. A. Rauwerda, and V. W. M. van Hinsbergh, “Decreased smooth muscle cell/extracellular matrix ratio of media of femoral artery in patients with atherosclerosis and hyperhomocysteinemia,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 4, pp. 573–577, 2001.
View at: Google Scholar
C. D. A. Stehouwer and C. van Guldener, “Does homocysteine cause hypertension?” Clinical Chemistry and Laboratory Medicine, vol. 41, no. 11, pp. 1408–1411, 2003.
View at: Publisher Site | Google Scholar
C. van Guldener, P. W. B. Nanayakkara, and C. D. A. Stehouwer, “Homocysteine and blood pressure,” Current Hypertension Reports, vol. 5, no. 1, pp. 26–31, 2003.
View at: Google Scholar
F. Locatelli, B. Canaud, K.-U. Eckardt, P. Stenvinkel, C. Wanner, and C. Zoccali, “The importance of diabetic nephropathy in current nephrological practice,” Nephrology Dialysis Transplantation, vol. 18, no. 9, pp. 1716–1725, 2003.
View at: Publisher Site | Google Scholar
D. Aronson, “Hyperglycemia and the pathobiology of diabetic complications,” Advances in Cardiology, vol. 45, pp. 1–16, 2008.
View at: Publisher Site | Google Scholar
T.-C. Lu, Z.-H. Wang, X. Feng et al., “Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy,” Kidney International, vol. 76, no. 1, pp. 63–71, 2009.
View at: Publisher Site | Google Scholar
M. Toyoda, B. Najafian, Y. Kim, M. L. Caramori, and M. Mauer, “Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy,” Diabetes, vol. 56, no. 8, pp. 2155–2160, 2007.
View at: Publisher Site | Google Scholar
F. Zheng, A. Fornoni, S. J. Elliot et al., “Upregulation of type I collagen by TGF-β in mesangial cells is blocked by PPARγ activation,” American Journal of Physiology, vol. 282, no. 4, pp. F639–F648, 2002.
View at: Google Scholar
R. Ohashi, H. Kitamura, and N. Yamanaka, “Peritubular capillary injury during the progression of experimental glomerulonephritis in rats,” Journal of the American Society of Nephrology, vol. 11, no. 1, pp. 47–56, 2000.
View at: Google Scholar
A. Shimizu, H. Kitamura, Y. Masuda, M. Ishizaki, Y. Sugisaki, and N. Yamanaka, “Rare glomerular capillary regeneration and subsequent capillary regression with endothelial cell apoptosis in progressive glomerulonephritis,” American Journal of Pathology, vol. 151, no. 5, pp. 1231–1239, 1997.
View at: Google Scholar
H.-C. Yang, L.-J. Ma, J. Ma, and A. B. Fogo, “Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis,” Kidney International, vol. 69, no. 10, pp. 1756–1764, 2006.
View at: Publisher Site | Google Scholar
A. C. Calkin, S. Giunti, K. A. Jandeleit-Dahm, T. J. Allen, M. E. Cooper, and M. C. Thomas, “PPAR-α and -γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse,” Nephrology Dialysis Transplantation, vol. 21, no. 9, pp. 2399–2405, 2006.
View at: Publisher Site | Google Scholar
P. Balakumar, M. Rose, S. S. Ganti, P. Krishan, and M. Singh, “PPAR dual agonists: are they opening Pandora's box?” Pharmacological Research, vol. 56, no. 2, pp. 91–98, 2007.
View at: Publisher Site | Google Scholar
H. Izzedine, V. Launay-Vacher, I. Buhaescu, A. Heurtier, A. Baumelou, and G. Deray, “PPARγ-agonists' renal effects,” Minerva Urologica e Nefrologica, vol. 57, no. 4, pp. 247–260, 2005.
View at: Google Scholar
S. Ohga, K. Shikata, K. Yozai et al., “Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation,” American Journal of Physiology, vol. 292, no. 4, pp. F1141–F1150, 2007.
View at: Publisher Site | Google Scholar
G. J. Ko, Y. S. Kang, S. Y. Han et al., “Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats,” Nephrology Dialysis Transplantation, vol. 23, no. 9, pp. 2750–2760, 2008.
View at: Publisher Site | Google Scholar
W. E. Rodriguez, N. Tyagi, I. G. Joshua et al., “Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus,” American Journal of Physiology, vol. 291, no. 3, pp. F694–F701, 2006.
View at: Publisher Site | Google Scholar
Y. Makita, D. K. Moczulski, J. Bochenski, A. M. Smiles, J. H. Warram, and A. S. Krolewski, “Methylenetetrahydrofolate reductase gene polymorphism and susceptibility to diabetic nephropathy in type 1 diabetes,” American Journal of Kidney Diseases, vol. 41, no. 6, pp. 1189–1194, 2003.
View at: Publisher Site | Google Scholar
O. Vaccaro, A. F. Perna, F. P. Mancini et al., “Plasma homocysteine and microvascular complications in type 1 diabetes,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 10, no. 6, pp. 297–304, 2000.
View at: Google Scholar
S. C. Tyagi, L. M. Smiley, V. S. Mujumdar, B. Clonts, and J. L. Parker, “Reduction-oxidation (Redox) and vascular tissue level of homocyst(e)ine in human coronary atherosclerotic lesions and role in extracellular matrix remodeling and vascular tone,” Molecular and Cellular Biochemistry, vol. 181, no. 1-2, pp. 107–116, 1998.
View at: Publisher Site | Google Scholar
R. Bissonnette, E. Treacy, R. Rozen, B. Boucher, J. S. Cohn, and J. Genest Jr., “Fenofibrate raises plasma homocysteine levels in the fasted and fed states,” Atherosclerosis, vol. 155, no. 2, pp. 455–462, 2001.
View at: Publisher Site | Google Scholar
K.-M. Lee, K. Y. Tsai, N. Wang, and D. E. Ingber, “Extracellular matrix and pulmonary hypertension: control of vascular smooth muscle cell contractility,” American Journal of Physiology, vol. 274, no. 1, pp. H76–H82, 1998.
View at: Google Scholar
T. M. Camp, L. M. Smiley, M. R. Hayden, and S. C. Tyagi, “Mechanism of matrix accumulation and glomerulosclerosis in spontaneously hypertensive rats,” Journal of Hypertension, vol. 21, no. 9, pp. 1719–1727, 2003.
View at: Publisher Site | Google Scholar
R. A. Kagan, M. Kinsel, K. Gloor et al., “Morphologic evidence suggestive of hypertension in western gray kangaroos (Macropus fuliginosus),” Veterinary Pathology, vol. 46, no. 5, pp. 977–984, 2009.
View at: Publisher Site | Google Scholar
J. Rysz, M. Banach, R. A. Stolarek et al., “Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy,” Journal of Nephrology, vol. 20, no. 4, pp. 444–452, 2007.
View at: Google Scholar
T. Endo, K. Nakabayashi, M. Sekiuchi, T. Kuroda, A. Soejima, and A. Yamada, “Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohistochemical staining,” Clinical and Experimental Nephrology, vol. 10, no. 4, pp. 253–261, 2006.
View at: Publisher Site | Google Scholar
I. Hirahara, M. Inoue, K. Okuda, Y. Ando, S. Muto, and E. Kusano, “The potential of matrix metalloproteinase-2 as a marker of peritoneal injury, increased solute transport, or progression to encapsulating peritoneal sclerosis during peritoneal dialysis—a multicentre study in Japan,” Nephrology Dialysis Transplantation, vol. 22, no. 2, pp. 560–567, 2007.
View at: Publisher Site | Google Scholar
H.-R. Chang, S.-F. Yang, M.-L. Li, C.-C. Lin, Y.-S. Hsieh, and J.-D. Lian, “Relationships between circulating matrix metalloproteinase-2 and -9 and renal function in patients with chronic kidney disease,” Clinica Chimica Acta, vol. 366, no. 1-2, pp. 243–248, 2006.
View at: Publisher Site | Google Scholar
P. Zaouio, J. F. Cantin, M. Alimardani-Bessette et al., “Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions,” Diabetes and Metabolism, vol. 26, supplement 4, pp. 25–29, 2000.
View at: Google Scholar
A. A. Eddy, H. Kim, J. Lopez-Guisa et al., “Interstitial fibrosis in mice with overload proteinuria: deficiency of TIMP-1 is not protective,” Kidney International, vol. 58, no. 2, pp. 618–628, 2000.
View at: Publisher Site | Google Scholar
H Hoppeler and S. R. Kayar, “Capillarity and oxidative capacity of muscles,” News in Physiological Sciences, vol. 3, pp. 113–116, 1988.
View at: Google Scholar
D. J. Pinsky, S. Patton, S. Mesaros et al., “Mechanical transduction of nitric oxide synthesis in the beating heart,” Circulation Research, vol. 81, no. 3, pp. 372–379, 1997.
View at: Google Scholar
W. E. Rodriguez, U. Sen, N. Tyagi et al., “PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice,” International Journal of Biological Sciences, vol. 4, no. 4, pp. 236–244, 2008.
View at: Google Scholar
C. D. A. Stehouwer and C. van Guldener, “Does homocysteine cause hypertension?” Clinical Chemistry and Laboratory Medicine, vol. 41, no. 11, pp. 1408–1411, 2003.
View at: Publisher Site | Google Scholar
H. Jakubowski, “Metabolism of homocysteine thiolactone in human cell cultures: possible mechanism for pathological consequences of elevated homocysteine levels,” Journal of Biological Chemistry, vol. 272, no. 3, pp. 1935–1942, 1997.
View at: Google Scholar
H. Jakubowski, “Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels,” FASEB Journal, vol. 13, no. 15, pp. 2277–2283, 1999.
View at: Google Scholar
H. Jakubowski, “The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease,” Journal of Physiology and Pharmacology, vol. 59, supplement 9, pp. 155–167, 2008.
View at: Google Scholar
H. Jakubowski, “Translational accuracy of aminoacyl-tRNA synthetases: implications for atherosclerosis,” Journal of Nutrition, vol. 131, no. 11, pp. 2983S–2987S, 2001.
View at: Google Scholar
H. Jakubowski, “Homocysteine is a protein amino acid in humans: implications for homocysteine-linked disease,” Journal of Biological Chemistry, vol. 277, no. 34, pp. 30425–30428, 2002.
View at: Publisher Site | Google Scholar
R. Głowacki and H. Jakubowski, “Cross-talk between Cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation,” Journal of Biological Chemistry, vol. 279, no. 12, pp. 10864–10871, 2004.
View at: Publisher Site | Google Scholar
H. Jakubowski, G. H. J. Boers, and K. A. Strauss, “Mutations in cystathionine β-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans,” FASEB Journal, vol. 22, no. 12, pp. 4071–4076, 2008.
View at: Publisher Site | Google Scholar
J. Perła-Kaján, O. Stanger, M. Łuczak et al., “Immunohistochemical detection of N-homocysteinylated proteins in humans and mice,” Biomedicine and Pharmacotherapy, vol. 62, no. 7, pp. 473–479, 2008.
View at: Publisher Site | Google Scholar
P. Frosst, H. J. Blom, R. Milos et al., “A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase,” Nature Genetics, vol. 10, no. 1, pp. 111–113, 1995.
View at: Google Scholar
J. Golledge and P. E. Norman, “Relationship between two sequence variations in the gene for peroxisome proliferator-activated receptor-gamma and plasma homocysteine concentration. Health in men study,” Human Genetics, vol. 123, no. 1, pp. 35–40, 2008.
View at: Publisher Site | Google Scholar
A. M. Sharma and B. Staels, “Review: peroxisome proliferator-activated receptor γ and adipose tissue—understanding obesity-related changes in regulation of lipid and glucose metabolism,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 2, pp. 386–395, 2007.
View at: Publisher Site | Google Scholar
S. N. Murthy, D. F. Obregon, N. N. Chattergoon et al., “Rosiglitazone reduces serum homocysteine levels, smooth muscle proliferation, and intimal hyperplasia in Sprague-Dawley rats fed a high methionine diet,” Metabolism, vol. 54, no. 5, pp. 645–652, 2005.
View at: Publisher Site | Google Scholar
M. Sahin, N. B. Tutuncu, D. Ertugrul, N. Tanaci, and N. D. Guvener, “Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus,” Journal of Diabetes and Its Complications, vol. 21, no. 2, pp. 118–123, 2007.
View at: Publisher Site | Google Scholar
G. Yang, L. Wu, B. Jiang et al., “H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase,” Science, vol. 322, no. 5901, pp. 587–590, 2008.
View at: Publisher Site | Google Scholar
R. Wang, “Hydrogen sulfide: a new EDRF,” Kidney International, vol. 76, no. 7, pp. 700–704, 2009.
View at: Publisher Site | Google Scholar
L. Chang, B. Geng, F. Yu et al., “Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats,” Amino Acids, vol. 34, no. 4, pp. 573–585, 2008.
View at: Publisher Site | Google Scholar
Y. Kimura and H. Kimura, “Hydrogen sulfide protects neurons from oxidative stress,” FASEB Journal, vol. 18, no. 10, pp. 1165–1167, 2004.
View at: Publisher Site | Google Scholar
D. Yonezawa, F. Sekiguchi, M. Miyamoto et al., “A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium,” Toxicology, vol. 241, no. 1-2, pp. 11–18, 2007.
View at: Publisher Site | Google Scholar
S.-K. Yan, T. Chang, H. Wang, L. Wu, R. Wang, and Q. H. Meng, “Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells,” Biochemical and Biophysical Research Communications, vol. 351, no. 2, pp. 485–491, 2006.
View at: Publisher Site | Google Scholar
P. Libby, “Inflammation in atherosclerosis,” Nature, vol. 420, no. 6917, pp. 868–874, 2002.
View at: Publisher Site | Google Scholar
M. Nava, Y. Quiroz, N. Vaziri, and B. Rodríguez-Iturbe, “Melatonin reduces renal interstitial inflammation and improves hypertension in spontaneously hypertensive rats,” American Journal of Physiology, vol. 284, no. 3, pp. F447–F454, 2003.
View at: Google Scholar
F. L. Sung, Y. L. Siow, G. Wang, E. G. Lynn, and K. O, “Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis,” Molecular and Cellular Biochemistry, vol. 216, no. 1-2, pp. 121–128, 2001.
View at: Publisher Site | Google Scholar
G. Wang, Y. L. Siow, and K. O, “Homocysteine stimulates nuclear factor κB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possible role for protein kinase C,” Biochemical Journal, vol. 352, no. 3, pp. 817–826, 2000.
View at: Publisher Site | Google Scholar
R. Poddar, N. Sivasubramanian, P. M. DiBello, K. Robinson, and D. W. Jacobsen, “Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells implications for vascular disease,” Circulation, vol. 103, no. 22, pp. 2717–2723, 2001.
View at: Google Scholar
G. Wang, C. W. H. Woo, F. L. Sung, Y. L. Siow, and K. O, “Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 11, pp. 1777–1783, 2002.
View at: Publisher Site | Google Scholar
G. Wang, Y. L. Siow, and K. O, “Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-κB in THP-1 macrophages,” American Journal of Physiology, vol. 280, no. 6, pp. H2840–H2847, 2001.
View at: Google Scholar
M. Kerkeni, M. Tnani, L. Chuniaud, A. Miled, K. Maaroufi, and F. Trivin, “Comparative study on in vitro effects of homocysteine thiolactone and homocysteine on HUVEC cells: evidence for a stronger proapoptotic and proinflammative homocysteine thiolactone,” Molecular and Cellular Biochemistry, vol. 291, no. 1-2, pp. 119–126, 2006.
View at: Publisher Site | Google Scholar
S. Najib and V. Sánchez-Margalet, “Homocysteine thiolactone inhibits insulin-stimulated DNA and protein synthesis: possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation,” Journal of Molecular Endocrinology, vol. 34, no. 1, pp. 119–126, 2005.
View at: Publisher Site | Google Scholar
E. Łowicka and J. Bełtowski, “Hydrogen sulfide (H2S)—the third gas of interest for pharmacologists,” Pharmacological Reports, vol. 59, no. 1, pp. 4–24, 2007.
View at: Google Scholar
R. Clarke, R. Collins, S. Lewington et al., “Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis,” Journal of the American Medical Association, vol. 288, no. 16, pp. 2015–2022, 2002.
View at: Google Scholar
M. Den Heijer, S. Lewington, and R. Clarke, “Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies,” Journal of Thrombosis and Haemostasis, vol. 3, no. 2, pp. 292–299, 2005.
View at: Publisher Site | Google Scholar
J. Marcus, M. J. Sarnak, and V. Menon, “Homocysteine lowering and cardiovascular disease risk: lost in translation,” Canadian Journal of Cardiology, vol. 23, no. 9, pp. 707–710, 2007.
View at: Google Scholar
E. Lonn, S. Yusuf, M. J. Arnold et al., “Homocysteine lowering with folic acid and B vitamins in vascular disease,” The New England Journal of Medicine, vol. 354, no. 15, pp. 1567–1577, 2006.
View at: Publisher Site | Google Scholar
K. H. Bønaa, I. Njølstad, P. M. Ueland et al., “Homocysteine lowering and cardiovascular events after acute myocardial infarction,” The New England Journal of Medicine, vol. 354, no. 15, pp. 1578–1588, 2006.
View at: Publisher Site | Google Scholar
M. den Heijer, H. P. J. Willems, H. J. Blom et al., “Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial,” Blood, vol. 109, no. 1, pp. 139–144, 2007.
View at: Publisher Site | Google Scholar
R. L. Jamison, P. Hartigan, J. S. Kaufman et al., “Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial,” Journal of the American Medical Association, vol. 298, no. 10, pp. 1163–1170, 2007.
View at: Publisher Site | Google Scholar
R. N. Rodionov and S. R. Lentz, “The homocysteine paradox,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 6, pp. 1031–1033, 2008.
View at: Publisher Site | Google Scholar
C. M. Albert, N. R. Cook, J. M. Gaziano et al., “Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial,” The Journal of American Medical Association, vol. 299, no. 17, pp. 2027–2036, 2008.
View at: Google Scholar
E. Lonn, “Homocysteine-lowering B vitamin therapy in cardiovascular prevention—wrong again?” The Journal of American Medical Association, vol. 299, no. 17, pp. 2086–2087, 2008.
View at: Google Scholar

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Copyright © 2010 Utpal Sen and Suresh C. Tyagi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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