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

57 Citations (Scopus)

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

Fingerprint

rab GTP-Binding Proteins
Transport Vesicles
Cardiomegaly
Cardiomyopathies
Muscle Cells
Protein Kinase C
Heart Failure
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Exocytosis
Dilated Cardiomyopathy
Atrial Natriuretic Factor
Myelin Sheath
Endocytosis
Transgenes
Cardiac Myocytes
Confocal Microscopy
Endoplasmic Reticulum
Adrenergic Receptors
Hypertrophy

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Wu, G., Yussman, M. G., Barrett, T. J., Hahn, H. S., Osinska, H., Hilliard, G. M., ... 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

Increased myocardial Rab GTPase expression : A consequence and cause of cardiomyopathy. / Wu, Guangyu; Yussman, Martin G.; Barrett, Thomas J.; Hahn, Harvey S.; Osinska, Hanna; Hilliard, George M.; Wang, Xuejun; Toyokawa, Tsuyoshi; Yatani, Atsuko; Lynch, Roy A.; Robbins, Jeffrey; Dorn, Gerald W.

In: Circulation research, Vol. 89, No. 12, 07.12.2001, p. 1130-1137.

Research output: Contribution to journalArticle

Wu, G, Yussman, MG, Barrett, TJ, Hahn, HS, Osinska, H, Hilliard, GM, Wang, X, Toyokawa, T, Yatani, A, Lynch, RA, Robbins, J & Dorn, GW 2001, 'Increased myocardial Rab GTPase expression: A consequence and cause of cardiomyopathy', Circulation research, vol. 89, no. 12, pp. 1130-1137. https://doi.org/10.1161/hh2401.100427
Wu G, Yussman MG, Barrett TJ, Hahn HS, Osinska H, Hilliard GM et al. Increased myocardial Rab GTPase expression: A consequence and cause of cardiomyopathy. Circulation research. 2001 Dec 7;89(12):1130-1137. https://doi.org/10.1161/hh2401.100427
Wu, Guangyu ; Yussman, Martin G. ; Barrett, Thomas J. ; Hahn, Harvey S. ; Osinska, Hanna ; Hilliard, George M. ; Wang, Xuejun ; Toyokawa, Tsuyoshi ; Yatani, Atsuko ; Lynch, Roy A. ; Robbins, Jeffrey ; Dorn, Gerald W. / Increased myocardial Rab GTPase expression : A consequence and cause of cardiomyopathy. In: Circulation research. 2001 ; Vol. 89, No. 12. pp. 1130-1137.
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