Simvastatin inhibits the additive activation of ERK1/2 and proliferation of rat vascular smooth muscle cells induced by combined mechanical stress and oxLDL through LOX-1 pathway.
Vein grafts interposed into arteries are susceptible to the development of atherosclerosis due to rapid increases in blood pressure. This process is accelerated in patients with hyperlipidemia. The molecular mechanism underlying this process is unknown. In this study, quiescent rat vascular smooth muscle cells (VSMCs) were treated in vitro with mechanical stretch stress (10% elongation) with and without oxLDL (25 μg/ml) in the presence and absence of simvastatin (2.5 μmol/L). The results demonstrate that stretch stress and oxLDL can each induce activation of ERK1/2 and Ki-67 expression in VSMCs, but the peak levels of ERK activation and Ki-67 expression were observed in groups subjected to both stretch stress and oxLDL. Simvastatin was found to inhibit increased ERK activation and Ki-67 expression in VSMCs subjected to stretch stress with or without oxLDL. Mechanically, simvastatin was also found to inhibit increased expression of LOX-1 (a receptor of oxLDL) in VSMCs subjected to stretch stress with or without oxLDL. Knockdown of LOX-1 via small interfering RNAs (siRNA-LOX-1) resulted in obvious inhibition of ERK activation in VSMCs subjected to stretch stress with and without oxLDL. These results suggest that combined stretch stress and oxLDL can additively promote the activation of ERK1/2 leading to accelerated proliferation of VSMCs (e.g. increased Ki-67 expression) via LOX-1 signal pathway. This was found to be partially inhibited by simvastatin. These results may provide important data for the treatment and prevention of hypertension with or without hyperlipidemia.
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Zhengyu
Z
Zhang
Min
M
Zhang
Yuhuang
Y
Li
Shuying
S
Liu
Suning
S
Ping
Jingjing
J
Wang
Fen
F
Ning
Fukang
F
Xie
Chaohong
C
Li
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D013314:Stress, Mechanical; D015854:Up-Regulation
D000924:Anticholesteremic Agents; D019394:Ki-67 Antigen; D008077:Lipoproteins, LDL; C495136:OLR1 protein, rat; D034741:RNA, Small Interfering; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D019821:Simvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3