Effects of sarcoplasmic reticulum Ca2+-ATPase overexpression in postinfarction rat myocytes.
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Previous studies in adult myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) demonstrated abnormal contractility and intracellular Ca2+ concentration ([Ca2+]i) homeostasis and decreased sarcoplasmic reticulum Ca2+-ATPase (SERCA2) expression and activity, but sarcoplasmic reticulum Ca2+ leak was unchanged. In the present study, we investigated whether SERCA2 overexpression in MI myocytes would restore contraction and [Ca2+]i transients to normal. Compared with sham-operated hearts, 3-wk MI hearts exhibited significantly higher left ventricular end-diastolic and end-systolic volumes but lower fractional shortening and ejection fraction, as measured by M-mode echocardiography. Seventy-two hours after adenovirus-mediated gene transfer, SERCA2 overexpression in 3-wk MI myocytes did not affect Na+-Ca2+ exchanger expression but restored the depressed SERCA2 levels toward those measured in sham myocytes. In addition, the reduced sarcoplasmic reticulum Ca2+ uptake in MI myocytes was improved to normal levels by SERCA2 overexpression. At extracellular Ca2+ concentration of 5 mM, the subnormal contraction and [Ca2+]i transient amplitudes in MI myocytes (compared with sham myocytes) were restored to normal by SERCA2 overexpression. However, at 0.6 mM extracellular Ca2+ concentration, the supernormal contraction and [Ca2+]i transient amplitudes in MI myocytes (compared with sham myocytes) were exacerbated by SERCA2 overexpression. We conclude that SERCA2 overexpression was only partially effective in ameliorating contraction and [Ca2+]i transient abnormalities in our rat model of ischemic cardiomyopathy. We suggest that other Ca2+ transport pathways, e.g., Na+-Ca2+ exchanger, may also play an important role in contractile and [Ca2+]i homeostatic abnormalities in MI myocytes.