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CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts. | LitMetric

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts.

Cell Death Dis

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA.

Published: May 2020

AI Article Synopsis

  • This study investigates the role of Ca/calmodulin-dependent kinase II (CaMKII) in activating the protease μ-calpain during heart injuries caused by ischemia/reperfusion.
  • Researchers used isolated rat hearts to analyze the effects of calcium flux on heart injury and found that inhibiting CaMKII reduced calpain activity and heart damage, indicating that CaMKII's action is not solely dependent on calcium leakage through the ryanodine receptor.
  • The study revealed that CaMKII autophosphorylation enhances its interaction with calpain, promoting heart injury, but a mutant form of CaMKII could prevent these harmful effects by disrupting their relationship, suggesting potential therapeutic targets for heart protection.

Article Abstract

Previous studies indicated that Ca/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca-regulated protease μ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca flux using ryanodine and thapsigargin failed to prevent Ca paradox-induced heart injury. In contrast, the Ca paradox increased CaMKII auto-phosphorylation at Thr, while the CaMKII inhibitor KN-62 and the Na/Ca exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242471PMC
http://dx.doi.org/10.1038/s41419-020-2605-yDOI Listing

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