Genetic and Pharmacological Inhibition of Rheb1-mTORC1 Signaling Exerts Cardioprotection against Adverse Cardiac Remodeling in Mice
Genetic and Pharmacological Inhibition of Rheb1-mTORC1 Signaling Exerts Cardioprotection against Adverse Cardiac Remodeling in Mice
复制标题
Rheb1-mTORC1 信号传导的遗传和药理学抑制可对小鼠的不良心脏重塑发挥心脏保护作用
DOI：
10.1016/j.ajpath.2013.02.012
复制
发表时间：
2013-06-01
影响因子：
6
通讯作者：
Li, Xinli
中科院分区：
文献类型：
--
作者：
Wu, Xiangqi;Cao, Yunshan;Li, Xinli
先前的研究表明，Rheb 1是大脑中哺乳动物TOR复合物1（mTORC 1）信号转导所必需的。然而，Rheb 1在心脏中的功能仍然是难以捉摸的。在本研究中，我们删除了心肌细胞中的Rheb 1，并发现降低Rheb 1水平对心肌梗死（MI）和压力超负荷（横向主动脉缩窄）小鼠模型的病理性重构具有心脏保护作用。心肌细胞Rheb/-缺失小鼠的心肌细胞凋亡减少，mTORC 1活性受到抑制，表明Rheb 1调节心肌中mTORC 1的激活。此外，我们证明了黄芪甲苷IV（As-IV）可以抑制mTORC 1，并且As-IV治疗显示出与Rheb 1基因抑制相似的对MI和横向主动脉收缩的保护作用。这项研究表明，Rheb 1是必不可少的mTORC 1在心肌细胞中的激活，并表明，靶向Rheb 1-mTORC 1信号转导，如通过As-IV治疗，可能是一种有效的治疗方法，用于治疗MI和肥大后的不良心脏重塑患者。
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 Rheb/-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.