Abstract
It is well‐established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin‐2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy‐induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE−/− mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c‐Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c‐Myc indirectly regulates MFN2 expression is duo to the binding of c‐Myc to DNMT1 promoter up‐regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy‐induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c‐Myc to DNMT1 promoter is a new and relevant molecular mechanism.
Highlights
Atherosclerosis is a chronic progressive disease which is character‐ ized by the formation of atheromatous plaque in the intimal layer that mainly derived from the deregulation of cell behaviour, such as the activation of macrophages and abnormal vascular smooth mus‐ cle cells (VSMCs) proliferation and so on.[1,2] It has been indicated that homocysteine (Hcy) is an independent risk factor for atherosclerosis and it can induce endothelial dysfunction, foam formation and pro‐ mote vascular smooth muscle cell (VSMC) proliferation.[3,4] As an important component of the me‐ dial layer of blood vessels, VSMCs migration and proliferation with subsequent formation of intimal thickening is important for the de‐ velopment of atherosclerotic lesions
These data supported the hypothesis that DNMT1 is responsible for the hypermethylation of MFN2 promoter, which leads to suppression of MFN2 transcription in VSMCs treated with Hcy during the atherosclerotic plaque formation
Atherosclerosis is a complex disease which begins with eccen‐ tric thickening of the intima, which is predominantly composed of VSMCs, mesenchymal intimal cells and inflammatory cells.[2]
Summary
Atherosclerosis is a chronic progressive disease which is character‐ ized by the formation of atheromatous plaque in the intimal layer that mainly derived from the deregulation of cell behaviour, such as the activation of macrophages and abnormal vascular smooth mus‐ cle cells (VSMCs) proliferation and so on.[1,2] It has been indicated that homocysteine (Hcy) is an independent risk factor for atherosclerosis and it can induce endothelial dysfunction, foam formation and pro‐ mote VSMC proliferation.[3,4] As an important component of the me‐ dial layer of blood vessels, VSMCs migration and proliferation with subsequent formation of intimal thickening is important for the de‐ velopment of atherosclerotic lesions. DNMT3b could be recruited to the promoter region of RAS association domain family1A (RASSF1A) by c‐Myc to silence its expression through DNA hypermethyla‐ tion.[19] A comprehensive understanding of this dynamic interplay will set the stage, for the design of novel treatment strat‐ egies, and for the discovery of pan‐cellular transcription factor regulatory strategies to predict disease risk, therapy response and patient prognosis[20] and the dynamics of the mode of binding to DNA has changed this postulate and paved the way for new thera‐ pies targeted against VSMCs proliferation. These findings shed new insight into the mechanism of Hcy‐induced VSMCs proliferation in atherosclerosis and may be a ther‐ apeutic tool in the treatment of Hcy‐induced cardiovascular diseases
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