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 SIRT1fox/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 E1αflox/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.