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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
Summary
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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