Genetic and Pharmacological Inhibition of Rheb1-mTORC1 Signaling Exerts Cardioprotection against Adverse Cardiac Remodeling in Mice

被引:66
作者
Wu, Xiangqi [1 ,2 ]
Cao, Yunshan [1 ,2 ]
Nie, Junwei [2 ]
Liu, Hailang [2 ]
Lu, Shuangshuang [2 ]
Hu, Xiaoshan [2 ]
Zhu, Jingai [2 ]
Zhao, Xia [2 ]
Chen, Jiandong [3 ]
Chen, Xiaohu [3 ]
Yang, Zhongzhou [2 ]
Li, Xinli [1 ]
机构
[1] Nanjing Med Univ, Affiliated Hosp 1, Dept Cardiol, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Univ, Minist Educ, Model Anim Res Ctr, Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China
[3] Nanjing Univ Tradit Chinese Med, Jiangsu Prov Tradit Chinese Med Hosp Affiliated, Nanjing, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
MYOCARDIAL-INFARCTION; HEART-FAILURE; ASTRAGALOSIDE IV; RAPAMYCIN; KINASE; HYPERTROPHY; ACTIVATION; PROTECTION; AGONISTS; GROWTH;
D O I
10.1016/j.ajpath.2013.02.012
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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.
引用
收藏
页码:2005 / 2014
页数:10
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