Protection of the enhanced Nrf2 deacetylation and its downstream transcriptional activity by SIRT1 in myocardial ischemia/reperfusion injury

Int J Cardiol. 2021 Nov 1:342:82-93. doi: 10.1016/j.ijcard.2021.08.007. Epub 2021 Aug 14.

Abstract

Nrf2, the master gene transcriptor of antioxidant proteins, and SIRT1, the unique Class III histone deacetylase of sirtuins, have been involved in protecting myocardial ischemia/reperfusion (MI/R) injury. However, whether the protective effect of SIRT1 is directly related to the deacetylation of Nrf2 in the pathology of MI/R remains to be investigated. The current study was designed to evaluate the regulation of Nrf2 deacetylation and transcriptional activity by SIRT1 in MI/R. Hypoxia/reoxygenation (H/R) cardiomyocytes and MI/R mice were used to assess the role of SIRT1 in Nrf2 activation. Oxidative stress, cardiac function, LDH release, ROS and infarct size were also evaluated. We found that Nrf2 physically interacted with SIRT1 not only in normal and H/R cardiomyocytes in vitro, but also in Sham or I/R hearts in vivo. Adenovirus induced SIRT1 overexpression resulted in protected H/R induced cell death, accompanied by declined LDH release. Through MI/R in vivo, cardiac overexpression of SIRT1 led to ameliorated cardiac function and infarct size, as well as the decreased cardiac oxidative stress. Notably, such beneficial actions of SIRT1 were blocked by the Nrf2 silence. Mechanically, acetylation of Nrf2 was significantly decreased by SIRT1 overexpression in cardiomyocytes or in whole hearts, which upregulated the downstream signaling pathway of Nrf2. Taken together, we uncovered a clue, for the first time that SIRT1 physically interacts with Nrf2. The cardioprotective effect of SIRT1 overexpression against MI/R is associated with the increased Nrf2 deacetylation and activity. These findings have offered a direct proof and new perspective of post-translational modification in the understanding of oxidative stress and MI/R treatment.

Keywords: Deacetylation; Myocardial ischemia/reperfusion; Nrf2; Oxidative stress; SIRT1.

MeSH terms

  • Animals
  • Apoptosis
  • Mice
  • Myocardial Reperfusion Injury* / genetics
  • Myocardial Reperfusion Injury* / metabolism
  • Myocytes, Cardiac / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1