Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Am J Physiol Cell Physiol. 2010 Jul;299(1):C119-27. doi: 10.1152/ajpcell.00429.2009. Epub 2010 Apr 7.
It is becoming increasingly clear that cholesterol-independent effects of statins also contribute to the cardioprotective effects, but these mechanisms remain poorly understood. We investigated the effects of lovastatin on vascular smooth muscle phenotype. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin induces vascular smooth muscle cell (VSMC) differentiation. We found that lovastatin also inhibits mTORC1 signaling and that this inhibition is required for VSMC differentiation. Lovastatin inhibition of mTORC1 was farnesylation dependent, suggesting the farnesylated G protein Rheb (Ras homologue enriched in brain), a known upstream activator of mTORC1. Rheb overexpression induced mTORC1 activity and repressed contractile protein expression, but a farnesylation-deficient mutant (C18S) elicited the opposite effect. Rheb knockdown with small interfering RNA was also sufficient to inhibit mTORC1 and induce contractile protein expression, and it prevented statin-induced VSMC differentiation. Notably, mTORC1 activity was elevated in VSMC isolated from an intimal hyperplastic patient lesion compared with normal media, and lovastatin treatment inhibited mTORC1 activity in these cultures. Furthermore, lovastatin inhibited mTORC1 activity and prevented the downregulation of contractile protein expression in an ex vivo angioplasty model. In conclusion, these findings illustrate a mechanism for the cardioprotective effects of lovastatin through inhibition of Rheb and mTORC1 and promotion of a differentiated VSMC phenotype.
越来越明显的是，他汀类药物的胆固醇非依赖性作用也有助于心脏保护作用，但这些机制仍知之甚少。我们研究了洛伐他汀对血管平滑肌表型的影响。我们之前已经表明，雷帕霉素靶蛋白复合物 1（mTORC1）的抑制作用与雷帕霉素诱导血管平滑肌细胞（VSMC）分化。我们发现洛伐他汀也抑制 mTORC1 信号，并且这种抑制作用是 VSMC 分化所必需的。洛伐他汀对 mTORC1 的抑制作用依赖于法尼基化，提示法尼基化 G 蛋白 Rheb（富含大脑的 Ras 同源物）是 mTORC1 的已知上游激活物。Rheb 的过表达诱导 mTORC1 活性并抑制收缩蛋白的表达，但法尼基化缺陷突变体（C18S）则产生相反的效果。用小干扰 RNA 敲低 Rheb 也足以抑制 mTORC1 并诱导收缩蛋白的表达，并防止他汀类药物诱导的 VSMC 分化。值得注意的是，与正常培养基相比，从内膜增生患者病变中分离的 VSMC 中的 mTORC1 活性升高，而洛伐他汀处理抑制了这些培养物中的 mTORC1 活性。此外，洛伐他汀抑制 mTORC1 活性并防止在离体血管成形术模型中收缩蛋白表达的下调。总之，这些发现说明了洛伐他汀通过抑制 Rheb 和 mTORC1 以及促进分化的 VSMC 表型来发挥心脏保护作用的机制。
