SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion

Ying Han; Weiju Sun; Di Ren; Jingwen Zhang; Zhibin He; Julia Fedorova; Xiaodong Sun; Fang Han; Ji Li

doi:10.1016/j.redox.2020.101538

SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion

Redox Biol. 2020 Jul:34:101538. doi: 10.1016/j.redox.2020.101538. Epub 2020 Apr 13.

Authors

Ying Han¹, Weiju Sun², Di Ren³, Jingwen Zhang³, Zhibin He³, Julia Fedorova³, Xiaodong Sun⁴, Fang Han⁴, Ji Li⁵

Affiliations

¹ Cardiovascular Department, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Surgery, University of South Florida, Tampa, USA.
² Department of Surgery, University of South Florida, Tampa, USA; Cardiovascular Department, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
³ Department of Surgery, University of South Florida, Tampa, USA.
⁴ Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, USA.
⁵ Department of Surgery, University of South Florida, Tampa, USA. Electronic address: jili@usf.edu.

Abstract

Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) inflammasome was emerged as a marker of metabolic dysregulation. We revealed that age-related Sirtuin-1 (SIRT1) modulates cardiac metabolism that medicated inflammatory response during ischemia and reperfusion (I/R) stress. We hypothesize that SIRT1 attenuates NLRP3 inflammasome-dependent inflammation and pyroptosis during myocardial I/R through metabolic modulation. C57BL/6J wild type (WT) mice, inducible cardiomyocyte specific SIRT1 knockout (icSIRT1 KO) and inducible cardiomyocyte specific PDH E1α knockout (icPDH E1α KO) mice were subjected to ligation and release of left anterior descending coronary artery for in vivo regional I/R models. The echocardiography measurement demonstrated that SIRT1 agonist SRT1720 (30 μg/g) improved cardiac systolic function during 45 min of ischemia and 6 h of reperfusion in C57BL/6J WT mice. The biochemical analysis showed that I/R triggered activation of cardiac pyruvate dehydrogenase (PDH), while SIRT1 agonist SRT1720 inhibited I/R-induced PDH activity and reduced production of reactive oxygen species (ROS) during myocardial I/R. Moreover, SRT1720 regulates PDH-related glucose oxidative metabolism to reduce NLRP3 inflammasome activation and pyroptosis in an Akt signaling dependent manner during I/R. Furthermore, an impaired Akt signaling was observed in icSIRT1 KO versus SIRT1^fox/flox mice under I/R stress. Intriguingly, we observed lower levels of ROS generation, decreased NLRP3 levels and less pyroptosis occurred in the icPDH E1α KO versus PDH E1α^flox/flox hearts during I/R. Taken together, the results indicate that SIRT1 agonism can inhibit activation of NLRP3 inflammasome via Akt-dependent metabolic regulation during ischemic insults by I/R.

Keywords: Ischemia/reperfusion; NLRP3 inflammasome; ROS; SIRT1 agonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Inflammasomes*
Ischemia
Mice
Mice, Inbred C57BL
Myocardial Reperfusion Injury* / drug therapy
Myocardial Reperfusion Injury* / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
Oxidoreductases
Pyruvates
Reperfusion
Sirtuin 1 / genetics

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Pyruvates
Oxidoreductases
Sirt1 protein, mouse
Sirtuin 1