AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol (January 18, 2008). doi:10.1152/ajpheart.01016.2007
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Submitted on September 3, 2007
Accepted on January 17, 2008

Is Reduced SERCA2a Expression Detrimental or Beneficial to Postischemic Cardiac Function and Injury? Evidence from Heterozygous SERCA2a Knockout Mice

M.A. Hassan Talukder1, Anuradha Kalyanasundaram2, Li Zuo3, Murugesan Velayutham3, Yoshinori Nishijima3, Muthu Periasamy4, and Jay L Zweier5*

1 Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
2 Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States
3 Columbus, Ohio, United States; Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States
4 Columbus, Ohio, United States; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States
5 Columbus, Ohio, United States; United States; Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States

* To whom correspondence should be addressed. E-mail: jay.zweier{at}osumc.edu.

Recent studies have demonstrated that increased expression of SERCA2a 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 utilized a heterozygous SERCA2a-knockout (SERCA2a+/-) mouse model, with decreased SERCA pump levels, and studied the effect of myocardial stunning (20-min ischemia) and I/R, infarction (30-min ischemia) 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 WT 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 smaller peak systolic and markedly higher diastolic intracellular Ca2+ in SERCA2a+/- hearts compared to WT hearts. Both at 30-min ischemia and 2-min reperfusion, intracellular Ca2+ levels were significantly higher in SERCA2a+/- hearts. EPR spin trapping showed 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.




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