CaMKII δ inhibition protects against myocardial ischemia/reperfusion injury: Role of Beclin-1-dependent autophagy.

This study was performed using isolated perfused rat hearts and H9c2 cardiac myoblasts. KN-93, but not KN-92, inhibited the phosphorylation of CaMKIIδ at Thr286 and its substrate phospholamban at Thr17 besides the CaMKIIδ activity in myocardial IR. KN-93, but not KN-92 significantly improved post-ischemic cardiac function and reduced cell death. In cultured H9c2 cardiac myoblasts, KN-93 or CaMKIIδ siRNA, but not KN-92, attenuated simulated IR (SIR)-induced cell death. Moreover, CaMKIIδ inhibition could alleviate IR-induced autophagic dysfunction as evidenced in reduced levels of Atg5, p62, and LC3BII in isolated rat hearts and H9c2 cardiac myoblasts. Furthermore, co-treatment with bafilomycin A1, a lysosomal inhibitor, in CaMKII inhibition-treated cells suggested that CaMKII inhibition alleviated autophagic flux. CaMKIIδ inhibition mitigated the phosphorylation of Beclin-1 at Ser90. As expected, Beclin-1 siRNA significantly decreased the levels of Beclin-1 and Beclin-1 phosphorylation accompanied by partial reductions in Atg5, LC3BII, p62, cleaved caspase-3 and cytochrome c. However, Beclin-1 siRNA had little effect on CaMKIIδ phosphorylation. Taken together, these results demonstrated that CaMKIIδ inhibition reduced myocardial IR injury by improving autophagy dysfunction, and that CaMKIIδ-induced autophagy dysfunction partially depended on the phosphorylation of Beclin-1. PMID: 32918874 [PubMed - as supplied by publisher]
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research