The mechanistic target of rapamycin complex 1 critically regulates the function of mononuclear phagocytes and promotes cardiac remodeling in acute ischemia
| Autor: | Xiang Luo, Dian J. Cao, Gui Hao Chen, Vincent Phan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Myocardial Infarction Myocardial Ischemia Inflammation mTORC1 030204 cardiovascular system & hematology Mechanistic Target of Rapamycin Complex 1 Article 03 medical and health sciences Mice 0302 clinical medicine Sense (molecular biology) Medicine Macrophage Animals Myocardial infarction Molecular Biology Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Phagocytes biology Ventricular Remodeling business.industry Macrophages Myocardium Heart medicine.disease Cell biology 030104 developmental biology biology.protein biological phenomena cell phenomena and immunity medicine.symptom Cardiology and Cardiovascular Medicine business Function (biology) Signal Transduction |
| Zdroj: | J Mol Cell Cardiol |
| Popis: | Monocytes and macrophages are cellular forces that drive and resolve inflammation triggered by myocardial ischemia. One of the most important yet least understood regulatory mechanisms is how these cells integrate cues from micro-milieu with their response that eventually determines the outcome of myocardial repair. In the current study, we investigate 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, a surprising finding considering these cells resided in an environment that was hypoxic and lack of energy and nutrients. Our data suggests that the cardiac monocytes and macrophages gained effector functions predominantly in the ischemic niche, further supporting the crucial role of the microenvironment in deciding their functions. 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 the ischemia milieu and adjust their function. |
| Databáze: | OpenAIRE |
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