Copyright © 2006, European Society of Cardiology
Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage
Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany
* Corresponding author. Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, D-35392 Giessen, Germany. Tel.: +49 6419947241; fax: +49 6419947219. Email address: yaser.abdallah{at}physiologie.med.uni-giessen.de
Objective Experimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective, but the underlying mechanisms are still unknown. In this study, we investigated in isolated rat cardiomyocytes subjected to hypoxia and reoxygenation whether administration of insulin during reoxygenation reduces reoxygenation-induced hypercontracture, a hallmark of acute reperfusion injury. The effects of insulin on potential pro-survival kinases, i.e., PI 3-kinase, NO synthase (eNOS), and cGMP-dependent protein kinase (PKG), and on cytosolic Ca2+ control in reoxygenated cardiomyocytes were investigated.
Results Administration of insulin (10mU/L) during reoxygenation protected cardiomyocytes against hypercontracture development (cell length as % of end-hypoxic length: control 61.6±3.2; insulin 76.3±2.9*; n=26; *p<0.05 vs. control). Cytosolic [Ca2+] recovery during the first 2min of reoxygenation was accelerated (fura-2 ratio after 2min of reoxygenation; control 1.01±0.05; insulin 0.79±0.04*; n=26; *p<0.05 vs. control). The beneficial effects of insulin on cytosolic [Ca2+] recovery and hypercontracture were suppressed in the presence of inhibitors of PI 3-kinase (LY294002, 1µM), eNOS (L-NMMA, 100µM), PKG (KT 5823, 1µM), or sarcoplasmic reticulum Ca2+ pump (SERCA) (thapsigargin, 150nM). Insulin increased phosphorylation and activity of eNOS and augmented phospholamban phosphorylation in reoxygenated cardiomyocytes. Correlated with phospholamban phosphorylation, insulin also augmented SR Ca2+ load.
Conclusions Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture. This is due to acceleration of cytosolic [Ca2+] recovery by enhanced Ca2+ sequestration into the sarcoplasmic reticulum via SERCA activation. This protective mechanism is activated through the survival pathway consisting of PI 3-kinase, eNOS, and PKG.
KEYWORDS Insulin; Calcium; Cardiomyocytes
Gerd Heusch, Universitätsklinikum Essen, handled this article as Guest Editor.
Time for primary review 19 days
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