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 alpha 1 (P4H alpha 1) is essential for collagen synthesis but the effect of statin on P4H alpha 1 is unknown. We hypothesize that simvastatin may increase the expression of P4H alpha 1 in atherosclerotic plaques and ox-LDL-stimulated human aortic smooth muscle cells (HASMCs). In HASMCs, ox-LDL suppressed P4H alpha 1 expression significantly with peak value occurring at 50 ug/ml treated for 8 h. Ox-LDL also inhibited the expression of type land 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 P4H alpha 1. 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 P4H alpha 1 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 P4H alpha 1 and collagen possibly due to decreased ox-LDL content and phosphorylation of p38 and ERK1/2 in plaques. Thus, simvastatin increases P4H alpha 1 and collagen expression in ox-LDL-stimulated HASMCs and atherosclerotic plaques via p38 MAPK and ERK1/2, thereby exerting a plaque stabilizing effect. (C) 2013 Elsevier Ltd. All rights reserved.