Published online before print October 18, 2001, doi: 10.1161/hh2401.100427
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Increased Myocardial Rab GTPase Expression
A Consequence and Cause of Cardiomyopathy
From the Departments of Medicine (G.W., M.G.Y., T.J.B., H.S.H., T.T., A.Y., R.A.L., G.W.D.) and Physiology (G.M.H.), University of Cincinnati Medical Center; and Division of Molecular Cardiovascular Biology (H.O., X.W., J.R.), Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to G.W. Dorn II, Division of Cardiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0542. E-mail dorngw{at}ucmail.uc.edu
The Ras-like Rab GTPases regulate vesicle transport in endocytosis and exocytosis. We found that cardiac Rabs1, 4, and 6 are upregulated in a dilated cardiomyopathy model overexpressing ß2-adrenergic receptors. To determine if increased Rab GTPase expression can contribute to cardiomyopathy, we transgenically overexpressed in mouse hearts prototypical Rab1a, the small G protein that regulates vesicle transport from endoplasmic reticulum to and through Golgi. In multiple independent mouse lines, Rab1a overexpression caused cardiac hypertrophy that progressed in a time- and transgene dose–dependent manner to heart failure. Isolated cardiac myocytes were hypertrophied and exhibited contractile depression with impaired calcium reuptake. Ultrastructural analysis revealed enlarged Golgi stacks and increased transitional vesicles in ventricular myocytes, with increased secretory atrial natriuretic peptide granules and degenerative myelin figures in atrial myocytes; immunogold studies localized Rab1a to these abnormal vesicular structures. A survey of hypertrophy signaling molecules revealed increased protein kinase C (PKC) 
and 
, and confocal microscopy showed abnormal subcellular distribution of PKC in Rab1a transgenics. These results indicate that increased expression of Rab1 GTPase in myocardium distorts subcellular localization of proteins and is sufficient to cause cardiac hypertrophy and failure.
Key Words: Rab1 GTPase • transgenic mouse • vesicle transport • cardiac hypertrophy • cardiomyopathy
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