Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII), regulated by inhibitor 1 of protein phosphatase 1 (I1PP1), is vital for maintaining cardiovascular homeostasis. However, the role and mechanism of I1PP1 against hypoxia-reoxygenation (H/R) injury in cardiomyocytes remain a question. In our study, after I1PP1 overexpression by adenovirus infection in the neonatal cardiomyocytes followed by hypoxia for 4 h and reoxygenation for 12 h, the CaMKIIδ alternative splicing subtype, ATP content, and lactate dehydrogenase (LDH) release were determined. CaMKII activity was evaluated by phosphoprotein phosphorylation at Thr17 (p-PLB Thr17), CaMKII phosphorylation (p-CaMKII), and CaMKII oxidation (ox-CaMKII). Reactive oxygen species (ROS), mitochondrial membrane potential, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expressions were assessed. Our study verified that I1PP1 overexpression attenuated the CaMKIIδ alternative splicing disorder; suppressed PLB phosphorylation at Thr17, p-CaMKII, and ox-CaMKII; decreased cell LDH release; increased ATP content; attenuated ROS production; increased mitochondrial membrane potential; and decreased DRP1 expression but increased OPA1 expression in the cardiomyocytes after H/R. Contrarily, CaMKIIδ alternative splicing disorder, LDH release, ATP reduction, and ROS accumulation were aggravated after H/R injury with the I1PP1 knockdown. Collectively, I1PP1 overexpression corrected disorders of CaMKIIδ alternative splicing, inhibited CaMKII phosphorylation, repressed CaMKII oxidation, suppressed ROS production, and attenuated cardiomyocyte H/R injury.
Highlights
Myocardial ischemia-reperfusion injury (MIRI) is a phenomenon wherein the myocardial function is not improved but aggravated immediately after blood perfusion is restored in the ischemic myocardium [1,2,3,4]
Reperfusion is essential for blood flow recovery in the myocardium, it might result in serious damage to the heart during myocardium ischemia and reperfusion
Our present results showed that hypoxia-reoxygenation caused a disorder of CaMKIIδ alternative splicing in the cardiomyocytes, which was characterized by decreased expression of the δA and δB subtypes but increased expression of δC
Summary
Myocardial ischemia-reperfusion injury (MIRI) is a phenomenon wherein the myocardial function is not improved but aggravated immediately after blood perfusion is restored in the ischemic myocardium [1,2,3,4]. MIRI is a complex pathophysiological process involving multiple factors, such as oxygenfree radicals, calcium overload, inflammation, apoptosis, and endothelial cell homeostasis imbalance [8,9,10], in which excess of oxygen-free radicals is the critical factor for reperfusion injury [11]. Calcium/calmodulin-dependent protein kinase II (CaMKII) is one serine-threonine protein kinase with multifunctions, which is abundant in the myocardium and other excitable tissues [13, 14]. CaMKIIδ is the most abundant subtype in the myocardium [15]. In the presence of alternative splicing, CaMKIIδ is capable of producing three splicing variants of δA, δB, and δC
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