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

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

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 β2-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) α and δ, and confocal microscopy showed abnormal subcellular distribution of PKCα 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.

Original languageEnglish (US)
Pages (from-to)1130-1137
Number of pages8
JournalCirculation research
Volume89
Issue number12
DOIs
StatePublished - Dec 7 2001

Keywords

  • Cardiac hypertrophy
  • Cardiomyopathy
  • Rab1 GTPase
  • Transgenic mouse
  • Vesicle transport

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Increased myocardial Rab GTPase expression: A consequence and cause of cardiomyopathy'. Together they form a unique fingerprint.

  • Cite this

    Wu, G., Yussman, M. G., Barrett, T. J., Hahn, H. S., Osinska, H., Hilliard, G. M., Wang, X., Toyokawa, T., Yatani, A., Lynch, R. A., Robbins, J., & Dorn, G. W. (2001). Increased myocardial Rab GTPase expression: A consequence and cause of cardiomyopathy. Circulation research, 89(12), 1130-1137. https://doi.org/10.1161/hh2401.100427