SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition

  • Biomed Pharmacother. 2019 Oct;118:109227. doi: 10.1016/j.biopha.2019.109227.
Zhen-Hua Liu  1 ,  Yanhong Zhang  1 ,  Xue Wang  2 ,  Xiao-Fang Fan  1 ,  Yuqing Zhang  3 ,  Xu Li  4 ,  Yong-Sheng Gong  1 ,  Li-Ping Han  5
Affiliations
  • 1. Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 2. Teaching Center of Medical Functional Experiment, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 3. Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 4. Department of Physiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 5. Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Physiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
PMID: 31351433 DOI: 10.1016/j.biopha.2019.109227
Abstract

Endothelial-to-mesenchymal transition (EndMT) is closely related to the pathogenesis of various diseases, including cardiac fibrosis. Transforming growth factor (TGF)-β1 strongly induces EndMT, and Sirtuin 1 (SIRT1) may play vital roles in TGF-β/Smad pathway inhibition. This study aimed to determine whether SIRT1 activation inhibits EndMT, thereby attenuating cardiac fibrosis. Cardiac fibrosis was induced in C57BL/6 mice by subcutaneously injecting isoproterenol. SIRT1 was activated and then suppressed by intraperitoneally injecting resveratrol (RSV) and EX527, respectively. EndMT was induced by adding TGF-β1 to H5V cells and measured by immunofluorescence and western blot. The role of SIRT1 in EndMT was determined by lentivirus-mediated overexpression of SIRT1. Interactions between SIRT1 and SMAD2/3 in the TGF-β/SMAD2/3 pathway were examined by immunoprecipitation. SIRT1 activation upregulated CD31 and vascular endothelial-cadherin, and downregulated α-smooth muscle actin, fibroblast-specific protein 1, and vimentin. SIRT1 upregulated and EX527 inhibited TGF-β Receptor 1 (TGF-βR1) and P-Smad2/3 expression, respectively. SIRT1 activation and overexpression by RSV/SRT2104 and lentivirus transfection, respectively, reduced TGF-β1-induced EndMT. SIRT1 and SMAD2/3 interaction was shown by immunoprecipitation in vivo and in vitro. TGF-βR1 and P-Smad2/3 expression was downregulated and SMAD2/3 nuclear translocation was inhibited. In conclusion, SIRT1 activated by RSV attenuated isoproterenol-induced cardiac fibrosis by regulating EndMT via the TGF-β/SMAD2/3 pathway.

Keywords
Cardiac fibrosis; EndMT; SIRT1; TGF-β/Smad2/3; VE-cadherin.
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