Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Abstract

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

“…The effects of NaHS and L-Cys ( Fig. 7) were markedly inhibited by both INDO (1 μM,°°°P < 0.001) and AACOCF 3 (1 μM; ### P < 0.001). In addition, NaHS (100 μM) and L-Cys (100 μM) by themselves did not affect TxB 2 production (Fig.…”

“…H 2 S gaseous transmitter | urinary 11-dehydro-TXB2 | cardiovascular events | DL-propargylglycine | aminooxyacetic acid H yperhomocysteinemia (HHcy) is a risk factor for neurovascular and cardiovascular disease associated with endothelial dysfunction and accelerated atherosclerosis (1)(2)(3). Many clinical and epidemiological studies have demonstrated a positive correlation between homocysteine (Hcy) plasma levels and cardiovascular disorders (4,5), leading to the general conclusion that Hcy is a prothrombotic factor (6)(7)(8).…”

Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow

“…It has also been reported that there is a link between XBP1 and human disease (16,17). Although ER stress is reported to be involved in atherosclerosis (18)(19)(20)(21)(22), the role of XBP1 in vascular disease has not been examined in detail. In the present study, we demonstrated that disturbed flow induces XBP1 splicing and sustained activation that led to EC apoptosis and the formation of atherosclerotic lesion in ApoE Ϫ/Ϫ mice.…”

Homocisteína e polimorfismos dos genes MTHFR e VEGF: impacto na doença arterial coronariana

“…Although some studies found evidence of an association between the polymorphic MTHFR 677T allele and vascular diseases, carotid atherosclerosis, occlusive arterial disease and myocardial infarction [15][16][17][30][31][32] , others did not confirm these hypotheses 11,33 . A b o u t 4 0 % o f p a t i e n t s w i t h C A D p r e s e n t hyperhomocysteinemia 34 . In our study, 49.7% of the patients with CAD and 45.2% of the controls showed Hcy concentrations >15 µmol/L, and this difference was not significant.…”