Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase.
BACKGROUND
Senescent hearts are characterized by diastolic dysfunction and a decrease in sarcoplasmic reticulum (SR) Ca(2+)-ATPase protein (SERCA2a).


RESULTS
To test the hypothesis that an increase in SERCA2a could improve cardiac function in senescent rats (age 26 months), we used a catheter-based technique of adenoviral gene transfer to achieve global myocardial transduction of SERCA2a in vivo. Adult rat hearts aged 6 months and senescent rat hearts infected with an adenovirus containing the reporter gene beta-galactosidase were used as controls. Two days after infection, parameters of systolic and diastolic function were measured in open-chest rats. Cardiac SERCA2a protein and ATPase activity were significantly decreased in senescent hearts compared with adult rats (Delta -30+/-4% and -49+/-5%) and were restored to adult levels after infection with Ad.SERCA2a. At baseline, left ventricular systolic pressure and +dP/dt were unaltered in senescent hearts; however, diastolic parameters were adversely affected with an increase in the left ventricular time constant of isovolumic relaxation and diastolic pressure (Delta +29+/-9% and +38+/-12%) and a decrease in -dP/dt (Delta -26+/-11%). Overexpression of SERCA2a did not significantly affect left ventricular systolic pressure but did increase +dP/dt (Delta +28+/-10%) in the senescent 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 contractility and diastolic function in senescent hearts.


CONCLUSIONS
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.
Schmidt
U
U
Cardiovascular Research Center, Anesthesia Department, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02129, USA.
del Monte
F
F
Miyamoto
M I
MI
Matsui
T
T
Gwathmey
J K
JK
Rosenzweig
A
A
Hajjar
R J
RJ
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D003971:Diastole; D018014:Gene Transfer Techniques; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D008297:Male; D009200:Myocardial Contraction; D051381:Rats; D011916:Rats, Inbred F344; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*
D000252:Calcium-Transporting ATPases