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Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice

¹Davis Heart and Lung Research Institute and The Division of Cardiovascular Medicine, Department of Internal Medicine, and ²Department of Cell Biology and Physiology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio

Submitted 3 September 2007 ; accepted in final form 17 January 2008

Recent studies have demonstrated that increased expression of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) 2a improves myocardial contractility and Ca²⁺ handling at baseline and in disease conditions, including myocardial ischemia-reperfusion (I/R). Conversely, it has also been reported that pharmacological inhibition of SERCA might improve postischemic function in stunned hearts or in isolated myocardium following I/R. The goal of this study was to test how decreases in SERCA pump level/activity affect cardiac function following I/R. To address this question, we used a heterozygous SERCA2a knockout (SERCA2a^+/–) mouse model with decreased SERCA pump levels and studied the effect of myocardial stunning (20-min ischemia followed by reperfusion) and infarction (30-min ischemia followed by reperfusion) following 60-min reperfusion. Our results demonstrate that postischemic myocardial relaxation was significantly impaired in SERCA2a^+/– hearts with both stunning and infarction protocols. Interestingly, postischemic recovery of contractile function was comparable in SERCA2a^+/– and wild-type hearts subjected to stunning. In contrast, following 30-min ischemia, postischemic contractile function was reduced in SERCA2a^+/– hearts with significantly larger infarction. Rhod-2 spectrofluorometry revealed significantly higher diastolic intracellular Ca²⁺ in SERCA2a^+/– hearts compared with wild-type hearts. Both at 30-min ischemia and 2-min reperfusion, intracellular Ca²⁺ levels were significantly higher in SERCA2a^+/– hearts. Electron paramagnetic resonance spin trapping showed a similar extent of postischemic free-radical generation in both strains. These data provide direct evidence that functional SERCA2a level, independent of oxidative stress, is crucial for postischemic myocardial function and salvage during I/R.

myocardial ischemia-reperfusion; sarco(endo)plasmic reticulum Ca²⁺-ATPase; calcium handling; free radicals; postischemic function

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