Aberrant DNA methylation of the PDGF gene in homocysteine‑mediated VSMC proliferation and its underlying mechanism.
It is well established that homocysteine (Hcy) is an independent risk factor for atherosclerosis (AS), which is characterized by vascular smooth muscle cell (VSMC) proliferation. However, the molecular mechanism underlying AS in VSMCs is yet to be elucidated. The aim of this study was to investigate the potential involvement of aberrant DNA methylation of the platelet‑derived growth factor (PDGF) gene in Hcy‑mediated VSMC proliferation and its underlying mechanism. Cultured human VSMCs were treated with varying concentrations of Hcy. VSMC proliferation, PDGF mRNA and protein expression and PDGF promoter demethylation showed a dose‑dependent increase with Hcy concentration, suggesting an association among them. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase, indicating that VSMC proliferation was increased under Hcy treatment. Furthermore, S‑adenosylhomocysteine (SAH) levels were observed to increase and those of S‑adenosylmethionine (SAM) were observed to decrease. The consequent decrease in the ratio of SAM/SAH may partially explain the hypomethylation of PDGF with Hcy treatment. Folate treatment exhibited an antagonistic effect against Hcy‑induced VSMC proliferation, aberrant PDGF methylation and PDGF expression. These data suggest that Hcy may stimulate VSMC proliferation through the PDGF signaling pathway by affecting the epigenetic regulation of PDGF through the demethylation of its promoter region. These findings may provide novel insight into the molecular association between aberrant PDGF gene demethylation and the proliferation of VSMCs in Hcy‑associated AS.
Department of Laboratory Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Xue-Bo
XB
Han
Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Hui-Ping
HP
Zhang
Department of Laboratory Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Cheng-Jian
CJ
Cao
Department of Laboratory Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Yan-Hua
YH
Wang
Department of Pathophysiology, Basic Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Jue
J
Tian
Department of Pathophysiology, Basic Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Xiao-Ling
XL
Yang
Department of Pathophysiology, Basic Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
An-Ning
AN
Yang
Center of Scientific Technology, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Jie
J
Wang
Department of Pathophysiology, Basic Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Yi-Deng
YD
Jiang
Department of Pathophysiology, Basic Medical School, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China.
Hua
H
Xu
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects*; D005492:Folic Acid / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine