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Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) has been shown to play a vital role in pathological events in myocardial ischemia/reperfusion (IR) injury. Dysregulation of autophagy in cardiomyocytes is implicated in myocardial IR injury. Here, we examined whether CaMKIIδ inhibition could protect against myocardial IR injury through alleviating autophagy dysfunction and evaluated the potential role of CaMKIIδ in Beclin-1-dependent autophagy in ischemia/reperfused hearts. 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. Copyright © 2020 Elsevier B.V. All rights reserved.


Lingheng Kong, Fengmei Xiong, Na Sun, Chennian Xu, Yulong Chen, Jian Yang, Xingli Su. CaMKIIδ inhibition protects against myocardial ischemia/reperfusion injury: Role of Beclin-1-dependent autophagy. European journal of pharmacology. 2020 Nov 05;886:173539

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PMID: 32918874

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