Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Am J Pathol. 2013 Jun;182(6):2005-14. doi: 10.1016/j.ajpath.2013.02.012. Epub 2013 Apr 6.
A previous study indicated that Rheb1 is required for mammalian target of TOR complex 1 (mTORC1) signaling in the brain. However, the function of Rheb1 in the heart is still elusive. In the present study, we deleted Rheb1 specifically in cardiomyocytes and found that reduced Rheb1 levels conferred cardioprotection against pathologic remodeling in myocardial infarction (MI) and pressure overload (transverse aortic constriction) mouse models. Cardiomyocyte apoptosis was reduced and mTORC1 activity was suppressed in cardiomyocyte Rheb1-deletion mice, suggesting that Rheb1 regulates mTORC1 activation in myocardium. Furthermore, we demonstrated that astragaloside IV (As-IV) could inhibit mTORC1, and As-IV treatment displayed similar protection against MI and transverse aortic constriction as Rheb1 genetic inhibition. This study indicates that Rheb1 is essential for mTORC1 activation in cardiomyocytes and suggests that targeting Rheb1-mTORC1 signaling, such as by As-IV treatment, may be an effective therapeutic method for treating patients with adverse cardiac remodeling after MI and hypertrophy.
先前的研究表明，Rheb1 是哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）在大脑中的信号通路所必需的。然而，Rheb1 在心脏中的功能仍然难以捉摸。在本研究中，我们特异性地在心肌细胞中删除 Rheb1，发现降低 Rheb1 水平可对心肌梗死（MI）和压力超负荷（横主动脉缩窄）小鼠模型中的病理性重塑提供心脏保护。心肌细胞 Rheb1 缺失小鼠的心肌细胞凋亡减少，mTORC1 活性受到抑制，表明 Rheb1 调节心肌中 mTORC1 的激活。此外，我们证明了黄芪甲苷 IV（As-IV）可以抑制 mTORC1，并且 As-IV 治疗对 MI 和横主动脉缩窄的保护作用与 Rheb1 基因抑制相似。这项研究表明 Rheb1 对于心肌细胞中 mTORC1 的激活是必需的，并表明靶向 Rheb1-mTORC1 信号通路，例如通过 As-IV 治疗，可能是治疗 MI 后和肥厚性心脏病患者不良心脏重塑的有效治疗方法。
