A Novel Molecular Mechanism of IKK ε -Mediated Akt/mTOR Inhibition in the Cardiomyocyte Autophagy after Myocardial Infarction.

Autophagy of cardiomyocytes after myocardial infarction (MI) is an important factor affecting the prognosis of MI. Excessive autophagy can lead to massive death of cardiomyocytes, which will seriously affect cardiac function. IKK epsilon plays a crucial role in the occurrence of autophagy, but the functional role in MI remains largely unknown. To evaluate the impact of IKK epsilon on the autophagy of cardiomyocytes after MI, MI was induced by surgical left anterior descending coronary artery ligation in IKK epsilon knockout (KO) mice and wild-type (WT) mice. Starvation of H9c2 cells with IKK epsilon siRNA and rescued with IKK epsilon overexpressed afterwards to test the mechanism of IKK epsilon in autophagyin vitro. Our results demonstrated that the expression of IKK epsilon was upregulated in mice myocardial tissues which were consistent with cardiomyocyte autophagy after MI. Significantly, the IKK epsilon KO mice showed increased infarct size, decreased viable cardiomyocytes, and exacerbated cardiac dysfunction when compared with the wild-type mice. Western blot and electron micrography analysis also revealed that loss of IKK epsilon induces excessive cardiomyocyte autophagy and reduced the expression of p-Akt and p-mTOR. Similar results were observed in IKK epsilon siRNA H9c2 cellsin vitrowhich were under starvation injury. Notably, the levels of p-Akt and p-mTOR can restore in IKK epsilon rescued cells. In conclusion, our results indicated that IKK epsilon protects cardiomyocyte survival by reduced autophagy following MI via regulation of the Akt/mTOR signaling pathway. Thus, our study suggests that IKK epsilon might represent a potential therapeutic target for the treatment of MI.