Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase

Background-Senescent hearts are characterized by diastolic dysfunction and a decrease in sarcoplasmic reticulum (SR) Ca2+-ATPase protein (SERCA2a). Me thods and Results-To test the hypothesis that an increase in SERCA2a could improve cardiac function in senescent rats (age 26 months), we used a cathe ter-based technique of adenoviral gene transfer to achieve global myocardia l transduction of SERCA2a in vivo. Adult rat hearts aged 6 months and senes cent rat hearts infected with an adenovirus containing the reporter gene be ta-galactosidase were used as controls. Two days after infection, parameter s of systolic and diastolic function were measured in open-chest rats. Card iac SERCA2a protein and ATPase activity were significantly decreased in sen escent hearts compared with adult rats (Delta-30+/-4% and -49+/-5%) and wer e restored to adult levels after infection with Ad.SERCA2a. At baseline, le ft ventricular systolic pressure and +dP/dt were unaltered in senescent hea rts; however, diastolic parameters were adversely affected with an increase in the left ventricular time constant of isovolumic relaxation and diastol ic pressure (il +29+/-9% and +38+/-12%) and a decrease in -dP/dt (Delta -26 +/-11%). Overexpression of SERCA2a did not significantly affect left ventri cular systolic pressure but did increase +dP/dt (Delta +28+/-10%) in the se nescent heart. Overexpression of SERCA2a restored the left ventricular time constant of isovolumic relaxation and -dP/dt to adult levels. Infection of senescent hearts with Ad.SERCA2a markedly improved rate-dependent contract ility and diastolic function in senescent hearts. Conclusions-These results support the hypothesis that decreased Ca2+-ATPase activity contributes to the functional abnormalities observed in senescent hearts and demonstrates that Ca2+ cycling proteins can be targeted in the senescent heart to improv e cardiac function.