Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Perna, Alessandra F.; Ingrosso, Diego; Zappia, Vincenzo; Galletti, Patrizia; Capasso, Giovambattista; Santo, Natale G. De

doi:10.1172/jci116485

Cited by 105 publications

(18 citation statements)

References 46 publications

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“…Elevated Hcy levels in patients are linked to increased SAH and impaired erythrocyte membrane protein methylation. 32 CBS-deficient mice have increased SAH levels and decreased DNA methylation. 8 Hcy arrests endothelial cell (EC) growth and increases cellular SAH in a cell type-specific way.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation

Wang

Jiang

Yang

et al. 2003

Blood

178

155

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Although hyperhomocysteinemia is an independent risk factor for cardiovascular disease, a direct role for homocysteine (Hcy) in this disease remains to be shown. Whereas diet-induced hyperhomocysteinemia promotes atherosclerosis in animal models, the effects of Hcy on atherogenesis in the absence of dietary perturbations is not known. We have generated double knock-out mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine ␤-synthase (CBS), which converts Hcy to cystathionine. ApoE ؊/؊ /CBS ؊/؊ mice developed aortic lesions even in the absence of dietary manipulation; lesion area and lesion cholesteryl ester (CE) and triglyceride (TG) contents increased with animal age and plasma Hcy levels. Plasma total cholesterol was significantly increased, whereas high density lipoprotein (HDL) cholesterol and TG concentrations of apoE ؊/؊ /CBS ؊/؊ mice were decreased. Cholesterol esterification and activities of enzymes catalyzing CE or TG formation in the vessel wall and in peritoneal macrophages were not changed by hyperhomocysteinemia. However, uptake of human acetyl-LDL, but not native low density lipoprotein (LDL), by mouse peritoneal macrophages was higher in the presence of hyperhomocysteinemia. These results suggest that isolated hyperhomocysteinemia is atherogenic and alters hepatic and macrophage lipoprotein metabolism, in part, by enhancing uptake of modified LDL. (Blood. 2003;101: 3901-3907)

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Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation

Wang

Jiang

Yang

et al. 2003

Blood

178

155

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“…SAH as a potent competitive inhibitor of methyltransferases may result in hypomethylation which causes DNA damage and cell apoptosis and induces tissue inflammation and sclerotic responses [101]. In patients with ESRD, a hypomethylation status of cellular proteins and DNA can be detected, as shown by high SAH intracellular concentrations, low SAM/SAH concentration ratios [18, 102], and inhibited protein methylation and repair [103]. This supports the view that the toxic actions of Hcys may be mediated by DNA hypomethylation in ESRD.…”

Section: Hypomethylationmentioning

confidence: 99%

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

Li²

2007

Am J Nephrol

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Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as lo- cal oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.

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“…We have demonstrated that Hcy, but not cysteine, arrested cell growth and increased cellular SAH concentration in endothelial cells (ECs), but not in vascular smooth muscle cells (VSMCs). 3 The hypomethylation hypothesis is supported by clinical studies showing that elevated Hcy levels in patients are linked to increased SAH and impaired erythrocyte membrane protein methylation, 4 and by animal studies showing that cystathionine ␤-synthase (CBS)-deficient mice have increased SAH levels and decreased DNA methylation. 5,6 Because damage to and impaired regeneration of ECs is a key feature of arteriosclerosis, growth inhibition of ECs may represent an important mechanism by which Hcy induces atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin Agene

Jamaluddin

Chen

Yang

et al. 2007

Blood

132

122

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We reported previously that homocysteine (Hcy) inhibits endothelial cell (EC) growth by transcriptional inhibition of the cyclin A gene via a hypomethylationrelated mechanism. In this study, we examined the effect of Hcy on epigenetic modification of the cyclin A gene and its biologic role in human ECs. Cyclin A mRNA levels were significantly suppressed by Hcy and a DNA methyltransferase inhibitor. The cyclin A promoter contains a CpG island spanning a 477-bp region (؊277/200). Bisulfite sequencing followed by polymerase chain reaction (PCR) amplification of the cyclin A promoter (؊267/37) showed that Hcy eliminated methylation at 2 CpG sites in the cyclin A promoter, one of which is located on the cycle-dependent element (CDE). Mutation of CG sequence on the CDE leads to a 6-fold increase in promoter activity. Hcy IntroductionHyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD), but the underlying mechanisms remain unclear. Although numerous studies have established that homocysteine (Hcy) has atherogenic effects on cultured vascular cells and in animal models of HHcy, the biochemical basis by which HHcy contributes to arteriosclerosis remains largely undefined.We initially proposed hypomethylation as a specific biochemical mechanism by which Hcy induces vascular injury. 1,2 Hcy can use adenosine, a normal constituent of all body fluids, to form S-adenosyl-homocysteine (SAH), a potent inhibitor of cellular methylation. We have demonstrated that Hcy, but not cysteine, arrested cell growth and increased cellular SAH concentration in endothelial cells (ECs), but not in vascular smooth muscle cells (VSMCs). 3 The hypomethylation hypothesis is supported by clinical studies showing that elevated Hcy levels in patients are linked to increased SAH and impaired erythrocyte membrane protein methylation, 4 and by animal studies showing that cystathionine ␤-synthase (CBS)-deficient mice have increased SAH levels and decreased DNA methylation. 5,6 Because damage to and impaired regeneration of ECs is a key feature of arteriosclerosis, growth inhibition of ECs may represent an important mechanism by which Hcy induces atherosclerosis.Our recent work suggested that the cyclin A gene is an important molecular target that mediates Hcy-induced EC growth inhibition. 7 Cyclin A (also named cyclin A2 as opposed to the male germ cell-specific cyclin A1) promotes both G1/S and G2/M transitions of the cell cycle in somatic cells. Cyclin A is expressed in late G1 and throughout S phase, and is controlled mainly at the transcriptional level. We have shown that the cyclin A gene is differentially regulated at a transcriptional level by Hcy in vascular cells. In ECs, clinically relevant concentrations of Hcy (10-50 M) arrested the cell cycle at G1/S transition via cyclinAtranscriptional inhibition. 7 In contrast, a supraphysiological concentration of Hcy (1 mM) activated cyclin A and promoted cell proliferation of VSMCs. 8 Because cyclin A transcriptional inhibition by Hcy is associated with SAH accum...

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Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine.

Cited by 105 publications

References 46 publications

Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation

Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin Agene

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