期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 159, 期 -, 页码 62-79出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2021.06.004
关键词
Myocardial infarction; Remodeling; Macrophage; mTORC1; Rapamycin
资金
- National Institutes of Health [R01 HL145298, K08 HL116801]
- VA Merit [5 I01 BX004562]
mTORC1 plays a crucial role in regulating the functions of cardiac monocytes and macrophages, and its inhibition promotes cardiac repair, reduces inflammatory injury, and decreases mortality from acute ischemia.
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..
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