Homocysteine-induced proliferation of vascular smooth muscle cells occurs via PTEN hypermethylation and is mitigated by Resveratrol

Abstract

Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in the development of atherosclerosis (AS), and the presence of homocysteine (Hcy) acts as an independent risk factor for AS. However, the underlying mechanisms remain to be elucidated. Phosphatase and tensin homologue on chromosome 10 (PTEN), is endogenously expressed in VSMCs and induces multiple signaling networks involved in cell proliferation, survival and inflammation, however, the specific role of PTEN is still unknown. The present study detected the proliferation ratio of VSMCs following treatment with Hcy and Resveratrol (RSV). In the 100 µM Hcy group, the proliferation ratio increased, and treatment with RSV decreased the proliferation ratio induced by Hcy. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to analyze PTEN expression, RSV treatment was associated with decreased PTEN expression levels in VSMCs. PTEN levels were decreased in Hcy treated cells, and the proliferation ratio of VSMCs were increased following treated with Hcy. To study the mechanism of regulation of PTEN by Hcy, the present study detected PTEN methylation levels in VSMCs, and PTEN DNA methylation levels were demonstrated to be increased in the 100 µM Hcy group, whereas treatment with RSV decreased the methylation status. DNA methyltransferase 1 is important role in the regulation of PTEN methylation. Overall, Hcy impacts the methylation status of PTEN, which is involved in cell proliferation, and induces the proliferation of VSMCs. This effect is alleviated by treatment with RSV, which exhibits an antagonistic mechanism against Hcy.

Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis

“…Hcy is an independent risk factor of atherosclerosis . Evidences revealed a marked stimulatory effect of Hcy on VSMC proliferation . It was well accepted that the transition of cell cycle from G0/G1 phase to S phase is one of the important characteristics of cell proliferation, which is accompanied by a great increase in DNA synthesis and abnormal expression of cell cycle proteins .…”

Resveratrol and Its Effects on the Vascular System

“…In vitro, resveratrol diminished the hypoxia-induced proliferation of human pulmonary artery-SMCs via inhibiting arginase II, an enzyme known to be upregulated in patients with pulmonary hypertension, and these effects were mediated via affecting PI3K-Akt signaling [107]. Resveratrol furthermore attenuated the homocysteine-induced proliferation of VSMCs, by reducing hypermethylation of phosphatase and tensin homologue on chromosome 10, PTEN [109]. In addition, in rats subjected to a chronic myocardial ischemia model, resveratrol induced the expression of Krüppel-like factor 15 (KLF15), known to play a protective role in the ischemic myocardium [110].…”

Resveratrol: Twenty Years of Growth, Development and Controversy

“…(1997), there is some evidence that resveratrol can function as a cardiovascular protectant. Resveratrol is reported to protect against atherosclerosis through inhibition of PTEN (Ma et al ., 2018); NOX1, MCP, AKT, ERK1/2, FOXO3A (Park et al ., 2009); CAV1 (Penumathsa et al ., 2008), and ERK1/2 signaling (El-Mowafy et al ., 2009), and activation of HO1, eNOS, VEGF (Penumathsa et al ., 2008) and pGC/kinase G signaling (El-Mowafy et al ., 2009). Its role in the protection against ischemic myocardial injury through inhibition of VEGF, HIF1α (Mukhopadhyay et al ., 2012); GSK3β (Goh et al ., 2007), and activation of KLF15 (Rogers and Otis, 2017); AKT, p38 (Goh et al ., 2007); MAPK signaling (Das et al ., 2006) has also been documented.…”