Homocysteine impaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signalling

Abstract

1. Hyperhomocysteinaemia (HHcy) is associated with endothelial dysfunction and has been recognized as a risk factor of cardiovascular disease. The present study aimed to investigate the effect of homocysteine (Hcy) on endothelial function in vivo and in vitro, and the underlying signalling pathways. 2. The HHcy animal model was established by intragastric administration with l-methionine in rats. Plasma Hcy and nitric oxide (NO) concentration were measured by fluorescence immunoassay or nitrate reductase method, respectively. Vasorelaxation in response to acetylcholine and sodium nitroprusside were carried out on aortic rings. Human umbilical vein endothelial cells (HUVEC) were treated with indicated concentrations of Hcy in the in vitro experiments. Intracellular NO level and NO concentration in culture medium were assayed. The alterations of possible signalling proteins were detected by western blot analysis. 3. l-methionine administration induced a significant increase in plasma Hcy and decrease in plasma NO. Endothelium-dependent relaxation of aortic rings in response to acetylcholine was impaired in l-methionine-administrated rats. The in vitro study showed that Hcy reduced both intracellular and culture medium NO levels. Furthermore, Hcy decreased phosphorylation of endothelial nitric oxide synthase (eNOS) at serine-1177 and phosphorylation of Akt at serine-473. Hcy-induced dephosphorylation of eNOS at Ser-1177 was partially reversed by insulin (Akt activator) and GF109203X (PKC inhibitor). Furthermore, Hcy reduced vascular endothelial growth factor (VEGF) expression in a dose-dependent manner. 4. In conclusion, Hcy impaired endothelial function through compromised VEGF/Akt/endothelial nitric oxide synthase signalling. These findings will be beneficial for further understanding the role of Hcy in cardiovascular disease.

Selenium Inhibits Homocysteine-Induced Endothelial Dysfunction and Apoptosis via Activation of AKT

“…Inhibition of AKT activation by dominant negative AKT mutants prevents enhanced NO synthesis mediated by eNOS [33]. Other studies indicated the role of AKT in Hcy-induced cell cycle G1 arrest [34] and impaired endothelial function [35]. Given these background, we hypothesized that Se may protect the function of endothelial cells in an AKT-dependent manner.…”

The relevance of epigenetics to occlusive cerebral and peripheral arterial disease

“…Hyperhomocysteinemia (HHcy) is associated with CVD and PAD [137,[142][143][144] and a deficiency of folic acid has been previously linked to endothelial dysfunction, atherosclerosis, stroke and CLI [145]. HHcy is associated with decreased levels of global genome-wide CpG methylation and promoter-specific gene methylation, promoting altered expression levels of a number of genes relevant to vascular damage [125,[146][147][148][149]. Furthermore, HHcy also suppresses angiogenesis, promotes SMC proliferation, promotes dyslipidaemia, stimulates vascular oxidative stress, and leads to impairment of EC regeneration and function [125,148].…”

“…HHcy is associated with decreased levels of global genome-wide CpG methylation and promoter-specific gene methylation, promoting altered expression levels of a number of genes relevant to vascular damage [125,[146][147][148][149]. Furthermore, HHcy also suppresses angiogenesis, promotes SMC proliferation, promotes dyslipidaemia, stimulates vascular oxidative stress, and leads to impairment of EC regeneration and function [125,148]. Advanced age is a major risk factor for CVD and PAD and aging is known to cause altered gene expression patterns due to epigenetic changes [150,151].…”

17β-estradiol attenuates homocysteine-induced oxidative stress and inflammatory response as well as MAPKs cascade via activating PI3-K/Akt signal transduction pathway in Raw 264.7 cells

“…Recently, evidence has suggested that PI3-K/Akt signaling pathway plays an important role in osteoclast differentiation and osteoclastogenesis [37][38][39]. Likewise, it is generally accepted that Hcy-induced activation of macrophages and endothelial cells is involved in the PI3K/Akt signaling pathway, ERK and oxidative stress [40][41][42].…”