Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Fu, Yi; Wang, Xian; Kong, Wei

doi:10.1111/bph.13988

Cited by 99 publications

(76 citation statements)

References 161 publications

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“…However, no significant difference was found in the distribution of APOE genotypes between the 2 groups ( p > 0.05). Neither ε2/ε2 nor ε4/ε4 was significantlyassociated with the risk of CAD (OR 0.96 [95% CI 0.54–1.71] and OR 1.49 [95% CI 0.57–3.91], respectively), which is consistent with previous reports [14, 20]. Conversely, a study conducted by Afroze et al [15]reported that ε4+ strongly increased the risk of CAD.…”

Section: Discussionsupporting

confidence: 89%

“…It has been proved through cell culture and animal studies that hyperhomocysteinemia damages arterial endothelial cells, and induces abnormal interaction with platelets and fibrinogen, eventually leading to the process of CAD [12]. Therefore, hyperhomocysteinemia is considered another risk factor for atherosclerosis [12-14]. Recent reports indicate that the single-nucleotide polymorphisms (SNPs) of MTHFR and APOE are associated with the risk of CAD, but the results are conflicting [15-21].…”

Section: Introductionmentioning

confidence: 99%

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A Case-Control Study of the Association of the Polymorphisms of MTHFR and APOE with Risk Factors and the Severity of Coronary Artery Disease

et al. 2019

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Objectives: To explore the association between single-nucleotide polymorphisms (SNPs) in MTHFR and APOE and the risk of CAD and, more importantly, the severity of CAD and the profile of serum lipids, we performed a case-control study in a Chinese Han population. Methods: A total of 1,207 cases of consecutive CAD-suspected inpatients were recruited, and 406 CAD cases and 231 non-CAD controls were enrolled for the final analysis after screening for exclusion criteria. All subjects had undergone coronary angiography, and the severity of CAD was evaluated by 2 cardiologists according to the Gensini scores. The genotypes of MTHFR and APOEwere detected using real-time PCR, and then verified by Sanger sequencing. Environmental risk factors, such as age, sex, smoking, alcohol consumption, hypertension, diabetes, dyslipidemia, and BMI were collected. Statistical analyses (the χ² test, binary logistic regression analysis, and ordinal polytomous logistic regression analysis) were performed with SPSS v16.0. Results: The genotypes ofall the subjects included in the CAD and non-CAD groups in this study were successfully detected, with an agreement of 100% with Sanger sequencing. The distributions of genotypes CT and TT at MTHFR C667T were higher in CAD cases than in non-CAD controls (OR 1.99, 95% CI 1.34–2.95; OR 1.77, 95% CI 1.18–2.67; p < 0.05), whereas genotype AC at MTHFR A1298Cwas lower in CAD cases (OR 0.71, 95% CI 0.50–1.02; p < 0.05). A significant association was observed in genotypes CT and TT at MTHFR C667T and the risk of CAD (OR 1.44, 95% CI 1.27–3.67; OR 1.56, 95% CI 0.88–2.78; p < 0.05). Both genotypes and alleles of APOE were comparable in the CAD cases and non-CAD controls (p > 0.05). The genotype TT at MTHFR C667T and ε4+ at APOE were more likely to be found in the CAD subgroup with a Gensini score ≥72 (p = 0.040 and p = 0.028, respectively). Meanwhile, in the patients with genotype TT,a higher level of serum Hcy was detected, while genotype ε4+ patients possessed higher levels of serum apolipoprotein E (ApoE) and low-density lipoprotein cholesterol (LDL-C) than other genotypes. Conclusion: This study revealed that the SNP site of MTHFR C667Tis associatedwith the risk of CAD in this Chinese Han population. In addition, the genotypes of TT in MTHFR C667T and ε4+in APOE may increase the severity of CAD, and higher Hcy, LDL-C, and ApoE levels may be involved in this pathogenic process.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A Case-Control Study of the Association of the Polymorphisms of MTHFR and APOE with Risk Factors and the Severity of Coronary Artery Disease

et al. 2019

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“…Impaired homocysteine metabolism is considered as the major cause of hyperhomocysteinemia. Folic acid and vitamin B12 are closely associated with maintaining homocysteine metabolism, and their supplementation reduces hyperhomocysteinemia [53]. This opens the possibility of using folic acid/vitamin B12 to potentially prevent/retard retinopathy in diabetic patients and alleviate their risk of losing vision.…”

Section: Resultsmentioning

confidence: 99%

Faulty homocysteine recycling in diabetic retinopathy

2020

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Background: Although hyperglycemia is the main instigator in the development of diabetic retinopathy, elevated circulating levels of a non-protein amino acid, homocysteine, are also associated with an increased risk of retinopathy. Homocysteine is recycled back to methionine by methylenetetrahydrofolate reductase (MTHFR) and/or transsulfurated by cystathionine β-synthase (CBS) to form cysteine. CBS and other transsulfuration enzyme cystathionine-γ-lyase (CSE), through desulfuration, generates H 2 S. Methionine cycle also regulates DNA methylation, an epigenetic modification associated with the gene suppression. The aim of this study was to investigate homocysteine and its metabolism in diabetic retinopathy. Methods: Homocysteine and H 2 S levels were analyzed in the retina, and CBS, CSE and MTHFR in the retinal microvasculature from human donors with established diabetic retinopathy. Mitochondrial damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics (fission-fusionmitophagy). DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation technique. The direct effect of homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells (HRECs) incubated with 100 μM L-homocysteine. Results: Compared to age-matched nondiabetic control human donors, retina from donors with established diabetic retinopathy had~3-fold higher homocysteine levels and~50% lower H 2 S levels. The enzymes important for both transsulfuration and remethylation of homocysteine including CBS, CSE and MTHFR, were 40-60% lower in the retinal microvasculature from diabetic retinopathy donors. While the mitochondrial fission protein, dynamin related protein 1, and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3 (LC3), were upregulated, the fusion protein mitofusin 2 was downregulated. In the same retinal microvessel preparations from donors with diabetic retinopathy, DNA at the promoters of CBS and MTHFR were hypermethylated. Incubation of HRECs with homocysteine increased reactive oxygen species and decreased transcripts of mtDNA-encoded CYTB. Conclusions: Compromised transsulfuration and remethylation processes play an important role in the poor removal of retinal homocysteine in diabetic patients. Thus, regulation of their homocysteine levels should ameliorate retinal mitochondrial damage, and by regulating DNA methylation status of the enzymes responsible for homocysteine transsulfuration and remethylation, should prevent excess accumulation of homocysteine.

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“…Studies have found that HHcy has a close relation with a variety of diseases [25] , such as cardiovascular disease, kidney disease, brain parenchymal disease, metabolic disease, and even tumors. The development of disease in HHcy involves endothelial dysfunction, thrombosis, thickening of blood vessel walls, oxidative stress, in ammatory responses, metabolic syndrome, and changes in disease-associated small mRNA [26] . Hcy is the intermediate product of methionine metabolism and transsulfuration [14] .…”

Section: Comparison Of Immune In Ammation and Oxidative Stress Indmentioning

confidence: 99%

Folic Acid Can Reduce Hyperhomocysteinemia-induced Vascular Damage by Immune/Inflammatory Response in Spontaneously Hypertensive Rats

Zhang¹,

li²,

Xing³

et al. 2020

Preprint

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Background Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. However, the mechanisms of HHcy-associated hypertensive vascular damage and the efficacy of folic acid (FA) as a treatment have not been fully elucidated. The aim of the present study was to evaluate the role of immune/inflammatory molecules and oxidizing factors in HHcy-associated hypertensive vascular damage, and to observe the intervention effect of FA on the two vascular injury factors. Methods Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were administered DL-Hcy intraperitoneally to mimic HHcy and hypertension associated with HHcy for 12 weeks. WKYs and SHRs were randomized into WKY group, HHcy group, SHR group, SHR + HHcy group and SHR + HHcy + FA group. Mean tail artery blood pressure, plasma Hcy, serum SOD and MDA of rats in each group were compared. The thoracic aorta and bilateral carotid artery of rats were harvested for morphometric and immunostaining analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of immune/inflammatory molecules such as TNF-α, IL-6, NF-κB p65/Rela and NF-κB2 and oxidative factors such as Nox2 and Nox4. Results We found that vascular inflammatory factors of vascular adhesion protein-1 (VAP-1), interleukin-6 (IL-6), and nuclear factor-κ-gene binding (NF-κB) p65/Rela in HHcy-associated hypertensive rats were significantly higher than those in SHRs (P༜0.05). While the oxidative stress indicators of Nox2 and Nox4 in HHcy-associated hypertensive rats were not significantly higher than those in SHRs (P༞0.05). Compared with SHRs, FA intervention in HHcy-associated hypertensive rats significantly increased serum superoxide dismutase (SOD) levels (P = 0.000) and significantly reduced vascular inflammatory factors of IL-6 and NF-κB p65/Rela (P༜0.05), but did not significantly change the oxidative stress indicators of Nox2 and Nox4 (P༞0.05). Conclusions HHcy-induced immune/inflammatory response plays a dominant role in vascular damage of HHcy-associated hypertensive rats. In addition to reducing the negative effects of HHcy, FA might involve unique antioxidant effects and inhibition of immune/inflammatory overreaction for HHcy-associated hypertensive rats.

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Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 99 publications

References 161 publications

A Case-Control Study of the Association of the Polymorphisms of <b><i>MTHFR</i></b> and <b><i>APOE</i></b> with Risk Factors and the Severity of Coronary Artery Disease

A Case-Control Study of the Association of the Polymorphisms of <b><i>MTHFR</i></b> and <b><i>APOE</i></b> with Risk Factors and the Severity of Coronary Artery Disease

Faulty homocysteine recycling in diabetic retinopathy

Folic Acid Can Reduce Hyperhomocysteinemia-induced Vascular Damage by Immune/Inflammatory Response in Spontaneously Hypertensive Rats

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