The mechanistic target of rapamycin complex 1 critically regulates the function of mononuclear phagocytes and promotes cardiac remodeling in acute ischemia

• Published in: Journal of molecular and cellular cardiology 2021-10, Vol.159, p.62-79
• Main Authors: Chen, GuiHao, Phan, Vincent, Luo, Xiang, Cao, Dian J.
• Format: Article
• Language: English
• Subjects: Animals; Heart - physiopathology; Macrophage; Macrophages - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; mTORC1; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Ischemia - metabolism; Myocardium - metabolism; Phagocytes - metabolism; Rapamycin; Remodeling; Signal Transduction - physiology; Ventricular Remodeling - physiology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2021.06.004

Monocytes and macrophages are cellular forces that drive and resolve inflammation triggered by acute myocardial ischemia. One of the most important but least understood regulatory mechanisms is how these cells sense cues from the micro-milieu and integrate environmental signals with their response that eventually determines the outcome of myocardial repair. In the current study, we investigated if the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) plays this role. We present evidence that support a robustly activated mTORC1 pathway in monocytes and macrophages in the infarcting myocardium.. Specific mTORC1 inhibition transformed the landscape of cardiac monocytes and macrophages into reparative cells that promoted myocardial healing. As the result, mTORC1 inhibition diminished remodeling and reduced mortality from acute ischemia by 80%. In conclusion, our data suggest a critical role of mTORC1 in regulating the functions of cardiac monocytes and macrophages, and specific mTORC1 inhibition protects the heart from inflammatory injury in acute ischemia. As mTOR/mTORC1 is a master regulator that integrates external signals with cellular responses, the study sheds light on how the cardiac monocytes and macrophages sense and respond to the ischemic environment.. [Display omitted] •mTORC1 is robustly activated in cardiac monocytes and macrophages in the infarcting myocardium.•Selective inhibition of mTORC1 by low dose rapamycin remarkably reduces mortality and improves cardiac function after myocardial infarction.•Cardiac protection by mTORC1 inhibition is achieved via promoting reparative macrophage phenotype in the ischemic niche.