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

Abstract

Previous studies indicated that Ca 2+ /calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca 2+-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 2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca 2+-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 2+ flux using ryanodine and thapsigargin failed to prevent Ca 2+ paradox-induced heart injury. In contrast, the Ca 2+ paradox increased CaMKII auto-phosphorylation at Thr 287 , while the CaMKII inhibitor KN-62 and the Na + /Ca 2+ 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 2+ 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.

miR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1

“…CAPN1 overactivation results in unregulated proteolysis and aberrant activation of signaling cascades, leading to cellular damage and ultimately cell death (42). CAPN1 is activated during heart and brain I/R injury due to increased intracellular calcium concentration, destroying cell structure and increasing apoptosis, reactive oxygen species, and inflammatory cytokines, while inhibiting CAPN1 protects the heart and brain from I/R injury (26)(27)(28). In liver I/R injury, CAPN1 activity significantly increased, and CAPN1 inhibition resulted in a significant decrease in liver apoptosis and necrosis (33).…”

“…Overactivation of calpain has been revealed to be involved in numerous diseases. The activity and expression of calpain-1 (CAPN1) has been revealed to increase after ischemia in the heart, liver, brain and other organs, while CAPN1 inhibition has been reported to alleviate organ I/R injury (26)(27)(28).…”

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

“…CaMKII is a protein kinase with key roles in various cardiac diseases, including heart failure, acute myocardial infarction, and malignant arrhythmias [41,42]. CaMKII consists of four isoforms: α, β, γ, and δ.…”

Baicalein, Baicalin, and Wogonin: Protective Effects against Ischemia‐Induced Neurodegeneration in the Brain and Retina

“…These neuroprotective effects exerted by baicalin have been found to be related to the inhibition of CaMKII-mediated downstream biochemical events [ 100 ]. CaMKII is an important protein involved in Ca 2+ /glutamate-mediated excitotoxicity under the stress of ischemia [ 87 , 102 ]. These findings imply that neuroprotective effects arising from baicalin are possibly related to its antiexcitotoxicity capacity.…”