(Circulation. 2000;101:790.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Restoration of Diastolic Function in Senescent Rat Hearts Through Adenoviral Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase
From the Cardiovascular Research Center and the Cardiology Division (F.d.M., M.I.M., T.M., A.R., R.J.H.) and Anesthesia Department (U.S.), Harvard Medical School and Massachusetts General Hospital; and Boston University School of Medicine (J.K.G.), Boston, Mass.
Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Boston, MA 02129. E-mail hajjar{at}cvrc.mgh.harvard.edu
Background—Senescent hearts are characterized by diastolic dysfunction and a decrease in sarcoplasmic reticulum (SR) Ca2+-ATPase protein (SERCA2a).
Methods and 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 ß-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
(
-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 ( +29±9% and +38±12%) and a decrease in -dP/dt (
-26±11%). Overexpression of SERCA2a did not significantly affect
left ventricular systolic pressure but did increase
+dP/dt ( +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 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 improve cardiac function.
Key Words: aging • gene therapy • heart failure • sarcoplasmic reticulum • diastole
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