MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
Biochem J. 2012 Jan 1;441(1):199-207. doi: 10.1042/BJ20110033.
In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.
在本研究中，我们观察到 MI（心肌梗死）在小鼠中迅速而强烈地激活核糖体蛋白 S6K（S6 激酶）。由于 S6K 的激活促进细胞生长，我们假设 S6K 活性的增加有助于 MI 后的病理性心脏重塑，并且抑制 S6K 激活可能防止异常的心脏重塑并改善心脏功能。在小鼠中，雷帕霉素的给药有效地抑制了心脏中的 S6K 激活，并显著改善了 MI 后的心脏功能。雷帕霉素处理的小鼠的心脏重量/体重比和纤维化面积显著降低。与载体处理的对照组相比，雷帕霉素处理的小鼠中观察到心肌细胞重构和细胞凋亡减少。一致地，用 PF-4708671 抑制 S6K 显示出与雷帕霉素相似的对 MI 的保护作用。从机制上讲，我们观察到雷帕霉素和 PF-4708671 处理的心脏中 Akt 的 Thr308 磷酸化和激活明显增强。在雷帕霉素给药存在的情况下，心肌细胞特异性缺失 PDK1（磷脂酰肌醇依赖性激酶 1）和 Akt1/3 消除了 MI 后的心脏保护作用。这些结果表明，S6K 抑制通过增强 Akt 信号通路对左心室功能产生有益影响，并减轻 MI 后小鼠的不良重塑，提示雷帕霉素和 PF-4708671 在 MI 后治疗患者具有治疗价值。
