(Circulation. 1999;100:2373.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Adenoviral Gene Transfer of Activated Phosphatidylinositol 3'-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro
From the Cardiovascular Research Center and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (T.M., L.L., F.d.M., R.J.H., A.R.); the Department of Pharmacology, Columbia University, New York, NY (T.F.F.); and the Laboratory of Biological Chemistry, University of Tokyo, Japan (Y.F.).
Correspondence to Anthony Rosenzweig, MD, Cardiovascular Research Center, MGH-East, 149 13th St, Room 4214, Charlestown, MA 02129. E-mail rosenzweig{at}helix.mgh.harvard.edu
Background—The intracellular signaling pathways that control cardiomyocyte apoptosis have not been fully defined. Because insulin-like growth factor-1 (IGF-1) prevents cardiomyocyte apoptosis, we examined the role of its downstream signaling molecules in an in vitro model of hypoxia-induced cardiomyocyte apoptosis.
Methods and Results—Treatment of rat neonatal cardiomyocytes with IGF-1 increased activity of both phosphatidylinositol 3' (PI 3)-kinase and its downstream target, Akt (also known as protein kinase B or PKB). Cardiomyocytes were subjected to hypoxia for 24 hours, and apoptosis was assessed by DNA laddering, TUNEL staining, and ELISA for histone-associated DNA fragments. IGF-1 treatment (100 nmol/L) reduced cardiomyocyte apoptosis, and this effect was inhibited by simultaneous treatment with a PI 3-kinase inhibitor. Cardiomyocytes were infected with either a control adenovirus (Ad.EGFP) or adenoviruses carrying constitutively active forms of PI 3-kinase (Ad.BD110) or Akt (Ad.myr-Akt-HA). Ad.BD110 significantly inhibited apoptosis of hypoxic cardiomyocytes compared with Ad.EGFP (61.0±4.6% less DNA fragmentation than in Ad.EGFP-infected cells, P<0.0001). Ad.myr-Akt-HA even more dramatically inhibited apoptosis of hypoxic cardiomyocytes (90.9±1.4% less DNA fragmentation than in controls, P<0.0001).
Conclusions—IGF-1 activates PI 3-kinase and Akt in cardiomyocytes. Activated PI 3-kinase and Akt are each sufficient to protect hypoxic cardiomyocytes against apoptosis in vitro. Adenoviral gene transfer provides a useful tool for investigating the role of these signaling pathways in cardiomyocyte apoptosis.
Key Words: kinase • viruses • growth substances • signal transduction
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S. Fukumoto, C.-M. Hsieh, K. Maemura, M. D. Layne, S.-F. Yet, K.-H. Lee, T. Matsui, A. Rosenzweig, W. G. Taylor, J. S. Rubin, et al. Akt Participation in the Wnt Signaling Pathway through Dishevelled J. Biol. Chem., May 11, 2001; 276(20): 17479 - 17483. [Abstract] [Full Text] [PDF]
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W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119. [Abstract] [Full Text] [PDF]
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D. Camper-Kirby, S. Welch, A. Walker, I. Shiraishi, K. D. R. Setchell, E. Schaefer, J. Kajstura, P. Anversa, and M. A. Sussman Myocardial Akt Activation and Gender : Increased Nuclear Activity in Females Versus Males Circ. Res., May 25, 2001; 88(10): 1020 - 1027. [Abstract] [Full Text] [PDF]
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