Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction.
Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca(2+) overload with reduced activity of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca(2+) homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca(2+) transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a(+/+)) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a(+/+) mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a(+/+) hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a(+/+) hearts. Importantly, intraischemic Ca(2+) levels were significantly lower in SERCA1a(+/+) hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a(+/+) hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca(2+) overload and thus provides potent myocardial protection.
Talukder
M A Hassan
MA
Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210, USA.
Kalyanasundaram
Anuradha
A
Zhao
Xue
X
Zuo
Li
L
Bhupathy
Poornima
P
Babu
Gopal J
GJ
Cardounel
Arturo J
AJ
Periasamy
Muthu
M
Zweier
Jay L
JL
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D003326:Coronary Circulation; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D005456:Fluorescent Dyes; D005609:Free Radicals / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
C506945:Atp2a1 protein, rat; D005456:Fluorescent Dyes; D005609:Free Radicals; D006575:Heterocyclic Compounds, 3-Ring; D007527:Isoenzymes; C068483:rhod-2; C002744:3-nitrotyrosine; D014443:Tyrosine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium