Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall

Balint, Brittany; Jepchumba, Viola Kosgei; Guéant, Jean‐Louis; Guéant-Rodríguez, Rosa-María

doi:10.1016/j.biochi.2020.02.012

Cited by 89 publications

(91 citation statements)

References 81 publications

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“…Several observations from in vitro and in vivo studies support the concept that hypomethylating stress contributes to the adverse vascular consequences of HHcy [1][2][3][6][7][8][9][10][11][12][13]. This possibility has been also supported by several human studies.…”

Section: Introductionmentioning

confidence: 68%

“…SAH is the precursor of Hcy that may accumulate in the setting of HHcy to cause hypomethylating stress, and this, in turn, may contribute to the vascular toxicity [2,3,6,7]. This possibility is based on the ability of SAH, once its intracellular concentration reaches a certain threshold, to inhibit the methyltransferase reactions that rely on SAM.…”

Section: Discussionmentioning

confidence: 99%

“…SAM is the methyl donor to several methyltransferases that target innumerous biomolecules, including DNA and proteins. Importantly, excess SAH inhibits the activities of these SAM-dependent methyltransferases, which results in decreases in the SAM:SAH ratio and intracellular methylating capacity [6,7]. SAH is further converted into Hcy by a reaction that is reversible and strongly favors SAH synthesis rather than hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

“…Several cell studies have documented the hypomethylating effect associated with decreased SAM: SAH ratios on epigenetically relevant targets that may contribute to the adverse vascular effects of Hcy accumulation [3,6,7]. Epigenetic modulators of gene expression include histone methylation [4].…”

Section: Introductionmentioning

confidence: 99%

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No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

et al. 2020

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Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (ApoE −/−) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

et al. 2020

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“…Finally, hyperhomocysteinemia is associated with chronic diseases such as endstage renal disease, severe hepatic dysfunction, diabetes mellitus, and hypothyroidism [53,54]. The vascular endothelium plays an important role in maintaining vascular homeostasis by regulating vascular tone, inflammation, and cell growth [58]. Endothelial dysfunction caused by hyperhomocysteinemia can trigger inflammation, apoptosis, and the subsequent formation of atherosclerotic lesions [59].…”

Section: Pathogenesis Of Hyperhomocysteinemia and Its Role As A Risk mentioning

confidence: 99%

Folic Acid Supplementation in Patients with Elevated Homocysteine Levels

et al. 2020

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Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

Carey

Fossati

2022

Alzheimer's & Dementia

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This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies.

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Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall

Cited by 89 publications

References 81 publications

No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

Folic Acid Supplementation in Patients with Elevated Homocysteine Levels

Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

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