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.
J Mol Cell Cardiol. 2013 Dec;65:43-50. doi: 10.1016/j.yjmcc.2013.09.010. Epub 2013 Sep 29.
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.
脯氨酰-4-羟化酶α1（P4Hα1）对于胶原合成至关重要，但他汀类药物对 P4Hα1 的影响尚不清楚。我们假设辛伐他汀可能会增加动脉粥样硬化斑块和氧化低密度脂蛋白（ox-LDL）刺激的人主动脉平滑肌细胞（HASMC）中 P4Hα1 的表达。在 HASMC 中，ox-LDL 显著抑制 P4Hα1 的表达，在 50ug/ml 处理 8 小时时达到峰值。ox-LDL 还抑制了 I 型和 III 型胶原的表达，并增加了 p38 MAPK 和 ERK1/2 的磷酸化水平，但 p38 和 ERK1/2 的阻断或沉默抑制了 ox-LDL 对 P4Hα1 的抑制作用。然后，在用或不用 ox-LDL（50ug/ml）刺激 HASMC 8 小时之前，用辛伐他汀预处理 1 小时。辛伐他汀通过抑制 ox-LDL 的摄取以及 p38 MAPK 和 ERK1/2 的激活，显著减弱了 ox-LDL 对 P4Hα1 和胶原产生的抑制作用。在载脂蛋白 E 缺陷小鼠中，辛伐他汀和 p38 以及 ERK1/2 的抑制剂显著增加了颈动脉斑块的稳定性。我们还发现，辛伐他汀显著增加了 P4Hα1 和胶原的表达，可能是由于斑块中 ox-LDL 含量和 p38 以及 ERK1/2 的磷酸化减少。因此，辛伐他汀通过 p38 MAPK 和 ERK1/2 增加 ox-LDL 刺激的 HASMC 和动脉粥样硬化斑块中的 P4Hα1 和胶原表达，从而发挥斑块稳定作用。
