The role of aberrant mTOR activation in heart failure
Description: Significant roles of mTOR complex 1 (mTORC1) in heart failure have been shown in animal models of heart failure. However, contribution of mTORC1 to pathogenesis of human heart failure has not been characterized. By use of endomyocardial biopsy specimens, we found that mTORC1 activity was higher in patients with heart failure than in controls. Furthermore, autophagy in cardiomyocytes was impaired by activation of necroptotic signals via suppression of autolysosome formation. Inhibition of mTORC1 by rapamycin restored the autophagic flux in cardiomyocytes. The effect of rampamycin was mediated by novel inhibitory phosphorylation of RIP1 and led to cardiomyocyte protection from necroptosis. Taken together, the findings suggest that aberrant mTORC1 activation is a therapeutic target in heart failure.
Amount: ¥4,810,000
Funding type: research
Funder scheme: Grant-in-Aid for Scientific Research (C)
Start date: 2016-04-01
End date: 2019-03-31
Investigator: Toshiyuki Yano
Institution: Sapporo Medical University
Funded outputs count: 14
Funder award ID: 16K09505
OpenAlex ID: G6582736112