In human and experimental models of heart failure, sarcoplasmic reticulum Ca 2؉ ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances in calcium metabolism have been shown to contribute significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constriction in rats. After 19 -23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25% decrease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n ‫؍‬ 13) or ␤-galactosidase (Ad.␤gal, n ‫؍‬ 14) by using a catheter-based technique. The failing hearts infected with Ad.␤gal were characterized by a significant decrease in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n ‫؍‬ 11). In addition, these failing hearts had reduced left-ventricular systolic pressure, maximal rate of left-ventricular pressure rise and decline (؉dP͞dt, ؊dP͞dt), and rate of isovolumic relaxation (). Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to nonfailing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in left-ventricular systolic pressure, ؉dP͞dt, ؊dP͞dt, and rate of isovolumic relaxation () normalizing them back to levels comparable to sham-operated rats. In this study, we show that in an animal model of heart failure where SERCA2a protein levels and activity are decreased and severe contractile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels. B oth contraction and relaxation abnormalities at the cardiac myocyte level have been identified in human and animal models of heart failure (1, 2). Trabeculae and isolated cardiac cells from failing hearts have characteristic functional abnormalities, which include an increase in diastolic Ca 2ϩ , an increase in the time course of Ca 2ϩ transient, and a decrease in sarcoplasmic reticulum (SR) Ca 2ϩ release (1-3). These abnormalities are especially accentuated at high frequencies of stimulation leading to the characteristic negative force-frequency relationship in failing myocardium (4).Because the SR plays a central role in controlling Ca 2ϩ movements in myocardial cells during excitation-contraction coupling, a large number of studies have been performed examining the expression and function of the SR Ca 2ϩ ATPase (SERCA2a)(5-9). SERCA2a activity and SR Ca 2ϩ uptake are reduced in failing hearts (9). This reduction in activity is generally, but not invariably, associated with reductions in SERCA2a mRNA and protein. Taken together, these results support the hypothesis that abnormal Ca 2ϩ handling in failing hearts is caused in part by a decrease in SERCA2a activity.To examine the importance of SERCA2a in the development of decompensated heart...

These results support the hypothesis that decreased Ca(2+)-ATPase activity contributes to the functional abnormalities observed in senescent hearts and demonstrates that Ca(2+) cycling proteins can be targeted in the senescent heart to improve cardiac function.