Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3

Abstract

Ischemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac JunD messenger ribonucleic acid expression was reduced while JunB increased. Cardiac-specific JunD overexpressing mice (JunDTg/0 ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.

Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats

“…Recent research proved that increasing SIRT3 levels alleviated mitochondrial dysfunction by normalizing mitochondrial bioenergetics in Parkinson's [29] and Alzheimer's diseases [30]. Moreover, overexpression of SIRT3 was shown to protect multiple organs from prolonged ischemia-reperfusion injury [31][32][33][34]. However, whether SIRT3-mediated mitophagy plays a part in hippocampus injury induced by HIR remains largely unclear.…”

JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

“…JunD also acts as a stress-responsive factor that induces redox imbalance and apoptosis in pancreatic b-cells (12). However, it will be of interest to determine whether JunD is involved in the cardiomyocyte-specific JunD overexpression reduced Sirt3 transcription, thus leading to mitochondrial dysfunction (53). Our results showed that JunD reversed the increase of Ucp2 induced by PA, which inhibits insulin secretion by reducing ATP synthesis (16), indicating that JunD might improve GSIS by changing mitochondrial ATP production.…”

Dexmedetomidine alleviates hepatic ischaemia‐reperfusion injury via the PI3K/AKT/Nrf2‐NLRP3 pathway

“…Functional rescue experiment revealed that overexpression of JUND partially reversed the protective effect of Dex on H/R cells. In consistency, JUND overexpression can increase the infarct size following myocardial I/R injury 50 …”

“…In consistency, JUND overexpression can increase the infarct size following myocardial I/R injury. 50 miR-494 attenuates hepatic I/R injury in a rat model by activating the PI3K/AKT pathway. 21 PI3K/AKT signalling plays a vital role in hepatic I/R injury by suppressing pro-apoptotic signals and inflammation.…”