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Originally published In Press as doi:10.1074/jbc.M201257200 on March 11, 2002

J. Biol. Chem., Vol. 277, Issue 21, 18979-18985, May 24, 2002
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Cardiomyocyte-specific Gene Expression Following Recombinant Adeno-associated Viral Vector Transduction*

Ryuichi AikawaDagger Dagger Dagger , Gordon S. HugginsDagger §||, and Richard O. Snyder**Dagger Dagger §§

From the Dagger  Cardiovascular Biology Laboratory, Harvard School of Public Health, ** Department of Pediatrics, Harvard Medical School and Dagger Dagger  Children's Hospital and the § Cardiac Unit, Massachusetts General Hospital, and the  Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

Recombinant adeno-associated viral (rAAV) vectors hold promise for delivering genes for heart diseases, but cardiac-specific expression by the use of rAAV has not been demonstrated. To achieve this goal rAAV vectors were generated expressing marker or potentially therapeutic genes under the control of the cardiac muscle-specific alpha myosin heavy chain (MHC) gene promoter. The rAAV-MHC vectors expressed in primary cardiomyocytes with similar kinetics to rAAV-CMV; however, expression by the rAAV-MHC vectors was restricted to cardiomyocytes. rAAV vectors have low cytotoxicity, and it is demonstrated here that rAAV fails to induce apoptosis in cardiomyocytes compared with a recombinant adenoviral vector. rAAV-MHC or rAAV-CMV vectors were administered to mice to determine the specificity of expression in vivo. The rAAV-MHC vectors expressed specifically in cardiomyocytes, whereas the control rAAV-CMV vector expressed in heart, skeletal muscle, and brain. rAAV-MHC transduction resulted in long term (16 weeks) expression of human growth hormone following intracardiac, yet not intramuscular, injection. Finally, we defined the minimal MHC enhancer/promoter sequences required for specific and robust in vivo expression in the context of a rAAV vector. For the first time we describe a panel of rAAV vectors capable of long term cardiac specific expression of intracellular and secreted proteins.

* This work was supported by Grant R01 HL54592-06 from the National Institutes of Health and by the Association Française contre les Myopathies.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115. Tel.: 617-636-2807; Fax: 617-432-2980; E-mail: ghuggins@hsph.harvard.edu.

§§ Present address: Dept. of Molecular Genetics and Microbiology, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610-0266.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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