Published online before print November 11, 2004, doi: 10.1161/01.RES.0000150366.08972.7f
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy
From the Heart and Vascular Center of the University of Cincinnati (F.S., A.O., H.S.H., E.W. B., R.A.L., Y.M., G.W.D) and the Division of Molecular Cardiovascular Biology (A.S., J.R.), Cincinnati Children’s Hospital Research Foundation, Ohio.
Correspondence to G.W. Dorn II, University of Cincinnati Heart and Vascular Center, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH 45267-0542. E-mail dorngw{at}ucmail.uc.edu
Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from 
-myosin heavy chain–directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Gq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional -MHC transgenic phenotypes.
Key Words: apoptosis • signal transduction • transgenic mice • hypertrophy
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