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Increased myocardial Rab GTPase expression: a consequence and cause of cardiomyopathy

G Wu1, M G Yussman, T J Barrett

  • 1Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.

Circulation Research
|December 12, 2001
PubMed

Insights

Increased Rab1 GTPase expression in the heart causes cardiac hypertrophy and heart failure by disrupting vesicle transport and protein localization. This study reveals a novel mechanism contributing to heart disease.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cardiovascular Biology

Background:

  • Ras-like Rab GTPases are crucial for intracellular vesicle transport.
  • Cardiac Rab GTPases (Rab1, 4, 6) are upregulated in a model of dilated cardiomyopathy.
  • The role of Rab GTPase overexpression in cardiomyopathy is not well understood.

Purpose of the Study:

  • To investigate if increased Rab GTPase expression contributes to cardiomyopathy.
  • To determine the effects of Rab1a overexpression on cardiac function and structure in mice.

Main Methods:

  • Transgenic overexpression of Rab1a in mouse hearts.
  • Assessment of cardiac function, including myocyte contractility and calcium handling.
  • Ultrastructural analysis of cardiac myocytes using electron microscopy.
  • Immunogold localization of Rab1a.
  • Analysis of hypertrophy signaling pathways, including protein kinase C (PKC).

Main Results:

  • Rab1a overexpression in mice led to cardiac hypertrophy, progressing to heart failure in a dose- and time-dependent manner.
  • Isolated cardiac myocytes showed hypertrophy, contractile dysfunction, and impaired calcium reuptake.
  • Ultrastructural changes included enlarged Golgi, increased vesicles, and abnormal secretory granules.
  • Rab1a localized to these abnormal vesicular structures.
  • Increased levels and abnormal subcellular distribution of PKC alpha and delta were observed.

Conclusions:

  • Increased Rab1 GTPase expression in the myocardium is sufficient to induce cardiac hypertrophy and heart failure.
  • Rab1a overexpression disrupts normal vesicle transport and protein localization within cardiac cells.
  • Aberrant Rab1a-mediated signaling contributes to the development of cardiomyopathy.

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