Simvastatin increases Prolyl-4-Hydroxylase α1 expression in atherosclerotic plaque and ox-LDL-stimulated human aortic smooth muscle cells via p38 MAPK and ERK1/2 signaling.
Prolyl-4-Hydroxylase α1 (P4Hα1) is essential for collagen synthesis but the effect of statin on P4Hα1 is unknown. We hypothesize that simvastatin may increase the expression of P4Hα1 in atherosclerotic plaques and ox-LDL-stimulated human aortic smooth muscle cells (HASMCs). In HASMCs, ox-LDL suppressed P4Hα1 expression significantly with peak value occurring at 50 ug/ml treated for 8h. Ox-LDL also inhibited the expression of type I and III collagen and increased the phosphorylation level of p38 MAPK and ERK1/2, but blockade or silencing of p38 and ERK1/2 inhibited the suppressive effect of ox-LDL on P4Hα1. Then HASMCs were stimulated with or without ox-LDL (50 ug/ml) for 8h after simvastatin pretreatment for 1h. Simvastatin significantly attenuated the suppressive effect of ox-LDL on P4Hα1 and collagen production by inhibiting ox-LDL uptake and the activation of p38 MAPK and ERK1/2. In apolipoprotein E-deficient mice, simvastatin and the inhibitors of p38 and ERK1/2 significantly increased the stability of the carotid plaques. We also found that simvastatin significantly increased the expression of P4Hα1 and collagen possibly due to decreased ox-LDL content and phosphorylation of p38 and ERK1/2 in plaques. Thus, simvastatin increases P4Hα1 and collagen expression in ox-LDL-stimulated HASMCs and atherosclerotic plaques via p38 MAPK and ERK1/2, thereby exerting a plaque stabilizing effect.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.
Kai
K
Zhang
Xiao
X
Meng
Jing
J
Kong
Fang-Fang
FF
Liu
Jian-Min
JM
Yang
Fei
F
Gao
Yun
Y
Zhang
Cheng
C
Zhang
D000818:Animals; D001011:Aorta / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000473:pathology; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D003094:Collagen; D019821:Simvastatin; D064828:Prolyl Hydroxylases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
Atherosclerosis; Mitogen-activated protein kinases; Oxidized low density lipoprotein; Prolyl-4-Hydroxylase α1; Simvastatin