Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage

被引:56
作者
Abdallah, Yaser [1 ]
Gkatzoflia, Anna [1 ]
Gligorievski, Dragan [1 ]
Kasseckert, Sascha [1 ]
Euler, Gerhild [1 ]
Schlueter, Klaus-Dieter [1 ]
Schaefer, Matthias [1 ]
Piper, Hans-Michael [1 ]
Schaefer, Claudia [1 ]
机构
[1] Univ Giessen, Inst Physiol, D-35392 Giessen, Germany
关键词
insulin; calcium; cardiomyocytes;
D O I
10.1016/j.cardiores.2006.02.020
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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, 1 mu M), eNOS (L-NMMA, 100 mu M), PKG (KT 5823, 1 mu M), or sarcoplasmic reticulurn 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. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:346 / 353
页数:8
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