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

摘要

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 dys- function observed in heart failure. We investigated whether increas- ing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constric- tion in rats. After 19--23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25/100 decrease in frattional shortening). rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a. n = 13) or p-galactosidase (Ad.pgal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad.beta-gal were character- ized 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 leff-ventricular syStoIic pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt -dP/dt. and rate of isovolumic relaxation (d. Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to non failing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in Ieff-ventricular systolic pressure, +dP/dt -dP/dt and rate of isovolumic relaxation (d 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 con- tradile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels.