(Circulation. 1997;96:400-403.)
© 1997 American Heart Association, Inc.
Articles |
Adenovirus-Mediated Gene Transfer Reconstitutes Depressed Sarcoplasmic Reticulum Ca2+-ATPase Levels and Shortens Prolonged Cardiac Myocyte Ca2+ Transients
From the Department of Medicine (F.J.G., H.H., M.M., M.R.S., W.H.D.), University of California at San Diego in La Jolla, and the Department of Biology (P.M.), San Diego State University (Calif).
Correspondence to Frank J. Giordano, MD, University of California at San Diego, Department of Medicine, 200 W Arbor Dr, San Diego, CA 92103-8411. E-mail fgiordano{at}ucsd.edu
Background Decreased expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase of the cardiac myocyte (SERCA2) and abnormal Ca2+ regulation have been independently linked to human heart failure. This study was designed to determine whether expression of a SERCA2 transgene could reconstitute depressed cardiac myocyte SERCA2 levels, augment SR Ca2+ uptake, and shorten prolonged excitation-contraction (EC)–associated Ca2+ transients in neonatal rat cardiac myocytes (NM).
Methods and Results Cultured NM were treated with phorbol-12-myristate-13-acetate (PMA), a compound that decreases endogenous SERCA2 expression and results in prolongation of EC-associated Ca2+ transients. PMA-treated NM had a 75% reduction in SERCA2 mRNA and a 40% reduction in SERCA2 protein levels. SERCA2 adenovirus infection increased SERCA2 mRNA expression to 2.5 times control and reconstituted SERCA2 protein levels in PMA-treated cells. This reconstitution was associated with a 32.4% reduction in the time for decline of the Indo-1 Ca2+ transient to half-maximum levels (t1/2 [Ca2+]i) (P<.05). A 34.5% augmentation of oxalate-facilitated SR Ca2+ uptake was also documented in SERCA2 adenovirus–infected cells (P<.05).
Conclusions Adenovirus-mediated expression of a SERCA2 transgene can reconstitute depressed endogenous SERCA2 levels, shorten prolonged Ca2+ transients, and augment SR Ca2+ uptake. It is conceivable that such an approach might be used in vivo to normalize altered Ca2+ regulation in human heart failure.
Key Words: genes • calcium • myocytes • adenovirus • molecular biology • cell
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