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

Abstract：

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 (10 mU/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 2 min of reoxygenation was accelerated (fura-2 ratio after 2 min 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 microM), eNOS (L-NMMA, 100 microM), PKG (KT 5823, 1 microM), or sarcoplasmic reticulum Ca2+ pump (SERCA) (thapsigargin, 150 nM). 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Abdallah Y,Gkatzoflia A,Gligorievski D,Kasseckert S,Euler G,Schlüter KD,Schäfer M,Piper HM,Schäfer C

doi

10.1016/j.cardiores.2006.02.020

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

346-53

issue

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(06)00082-4

journal_volume

pub_type

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