Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure

In human and experimental models of heart failure, sarcoplasmic reticulum C a2+ ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium h andling. The disturbances in calcium metabolism have been shown to contribu te significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricul ar function in an animal model of heart failure obtained by creating ascend ing aortic constriction in rats. After 19-23 wk of banding during the trans ition from compensated hypertrophy to heart failure (documented by >25% dec rease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosi dase (Ad.beta gal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad.beta gal were characterized by a significant decre ase in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n = 11). In addition, these failing hearts h ad reduced left-ventricular systolic: pressure, maximal rate of left-ventri cular pressure rise and decline (+dP/dt, -dP/dt), and rate of isovolumic: r elaxation (tau). 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 pressur e, +dP/dt, -dP/dt, and rate of isovolumic relaxation (tau) normalizing them back to levels comparable to sham-operated rats. In this study, we show th at in an animal model of heart failure where SERCA2a protein levels and act ivity are decreased and severe contractile dysfunction is present, overexpr ession of SERCA2a in vivo restores both systolic and diastolic function to normal levels.