2. Academic Validation
  3. mTOR contributes to endothelium-dependent vasorelaxation by promoting eNOS expression and preventing eNOS uncoupling

mTOR contributes to endothelium-dependent vasorelaxation by promoting eNOS expression and preventing eNOS uncoupling

  • Commun Biol. 2022 Jul 22;5(1):726. doi: 10.1038/s42003-022-03653-w.
Yiying Wang 1 2,  Qiannan Li 1 2,  Zhiyang Zhang 1 2,  Kai Peng 1 2,  Dai-Min Zhang 3 4,  Qianlu Yang 1 2,  Anthony G Passerini 5,  Scott I Simon 5,  ChongXiu Sun 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
  • 2 Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing, China.
  • 3 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4 Department of Cardiology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
  • 5 Department of Biomedical Engineering, University of California Davis, Davis, CA, USA.
  • 6 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. cxsun@njmu.edu.cn.
  • 7 Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing, China. cxsun@njmu.edu.cn.
PMID: 35869262 DOI: 10.1038/s42003-022-03653-w
Abstract

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of mTOR to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and NOX2 upregulation contributes to the excessive generation of Reactive Oxygen Species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of NOX2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

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