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 8 h. 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 8 h after simvastatin pretreatment for 1 h. 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.