This Article Full Text Full Text (PDF) All Versions of this Article: 89/12/1130    most recent hh2401.100427v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, G. Articles by Dorn, G. W. Search for Related Content PubMed PubMed Citation Articles by Wu, G. Articles by Dorn, G. W., II Related Collections Structure Animal models of human disease Physiological and pathological control of gene expression

(Circulation Research. 2001;89:1130.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Increased Myocardial Rab GTPase Expression

A Consequence and Cause of Cardiomyopathy

Guangyu Wu^*, Martin G. Yussman^*, Thomas J. Barrett^*, Harvey S. Hahn, Hanna Osinska, George M. Hilliard, Xuejun Wang, Tsuyoshi Toyokawa, Atsuko Yatani, Roy A. Lynch, Jeffrey Robbins, Gerald W. Dorn, II

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

This article has been cited by other articles:

				X. Zhang, G. Wang, D. J. Dupre, Y. Feng, M. Robitaille, E. Lazartigues, Y.-H. Feng, T. E. Hebert, and G. Wu Rab1 GTPase and Dimerization in the Cell Surface Expression of Angiotensin II Type 2 Receptor J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 109 - 117. [Abstract] [Full Text] [PDF]

				D. P. McEwen, S. M. Schumacher, Q. Li, M. D. Benson, J. A. Iniguez-Lluhi, K. M. Van Genderen, and J. R. Martens Rab-GTPase-dependent Endocytic Recycling of KV1.5 in Atrial Myocytes J. Biol. Chem., October 5, 2007; 282(40): 29612 - 29620. [Abstract] [Full Text] [PDF]

				C. M. Filipeanu, F. Zhou, E. K. Fugetta, and G. Wu Differential Regulation of the Cell-Surface Targeting and Function of beta- and {alpha}1-Adrenergic Receptors by Rab1 GTPase in Cardiac Myocytes Mol. Pharmacol., May 1, 2006; 69(5): 1571 - 1578. [Abstract] [Full Text] [PDF]

				C. M. Filipeanu, F. Zhou, M. L. Lam, K. E. Kerut, W. C. Claycomb, and G. Wu Enhancement of the Recycling and Activation of beta-Adrenergic Receptor by Rab4 GTPase in Cardiac Myocytes J. Biol. Chem., April 21, 2006; 281(16): 11097 - 11103. [Abstract] [Full Text] [PDF]

				J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]

				C. Gurkan, H. Lapp, C. Alory, A. I. Su, J. B. Hogenesch, and W. E. Balch Large-Scale Profiling of Rab GTPase Trafficking Networks: The Membrome Mol. Biol. Cell, August 1, 2005; 16(8): 3847 - 3864. [Abstract] [Full Text] [PDF]

				F. Syed, A. Odley, H. S. Hahn, E. W. Brunskill, R. A. Lynch, Y. Marreez, A. Sanbe, J. Robbins, and G. W. Dorn II Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy Circ. Res., December 10, 2004; 95(12): 1200 - 1206. [Abstract] [Full Text] [PDF]

				C. M. Filipeanu, F. Zhou, W. C. Claycomb, and G. Wu Regulation of the Cell Surface Expression and Function of Angiotensin II Type 1 Receptor by Rab1-mediated Endoplasmic Reticulum-to-Golgi Transport in Cardiac Myocytes J. Biol. Chem., September 24, 2004; 279(39): 41077 - 41084. [Abstract] [Full Text] [PDF]

				H. Hamada, M. Suzuki, S. Yuasa, N. Mimura, N. Shinozuka, Y. Takada, M. Suzuki, T. Nishino, H. Nakaya, H. Koseki, et al. Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice Mol. Cell. Biol., September 15, 2004; 24(18): 8007 - 8017. [Abstract] [Full Text] [PDF]

				M. T. Duvernay, F. Zhou, and G. Wu A Conserved Motif for the Transport of G Protein-coupled Receptors from the Endoplasmic Reticulum to the Cell Surface J. Biol. Chem., July 16, 2004; 279(29): 30741 - 30750. [Abstract] [Full Text] [PDF]

				A. Odley, H. S. Hahn, R. A. Lynch, Y. Marreez, H. Osinska, J. Robbins, and G. W. Dorn II Regulation of cardiac contractility by Rab4-modulated {beta}2-adrenergic receptor recycling PNAS, May 4, 2004; 101(18): 7082 - 7087. [Abstract] [Full Text] [PDF]

				G. Wu, G. Zhao, and Y. He Distinct Pathways for the Trafficking of Angiotensin II and Adrenergic Receptors from the Endoplasmic Reticulum to the Cell Surface: Rab1-INDEPENDENT TRANSPORT OF A G PROTEIN-COUPLED RECEPTOR J. Biol. Chem., November 21, 2003; 278(47): 47062 - 47069. [Abstract] [Full Text] [PDF]

				G. W. Dorn II, J. Robbins, and P. H. Sugden Phenotyping Hypertrophy: Eschew Obfuscation Circ. Res., June 13, 2003; 92(11): 1171 - 1175. [Full Text] [PDF]

				R. A. Lynch, L. Wagoner, S. Li, L. Sparks, J. Molkentin, and G. W. Dorn II Novel and nondetected human signaling protein polymorphisms Physiol Genomics, September 3, 2002; 10(3): 159 - 168. [Abstract] [Full Text] [PDF]

				A. J. Muslin Road Rage: Cardiac Rab1 and ER-to-Golgi Traffic Circ. Res., December 7, 2001; 89(12): 1087 - 1088. [Full Text] [PDF]