The development of cardiac hypertrophy is mediated, in part, by increase in NADPH oxidase activity and myocardial oxidative stress. The Rhp GTPase, Rac, regulates NADPH oxidase activity through interaction with gp91phox and p67phox (in which "phox" is phagocyte oxidase). However, it is not known which Rac isoform mediates this effect in the heart. Here we show that Rac1 is critical for generating oxidative stress and producing cardiac hypertrophy in the adult heart. The Rad gene was temporally and specifically deleted in adult mouse cardiomyocytes (c-Rac1-/-). Compared with wild-type or Rac1 heterozygous mice, the hearts of c-Rac1 -/- mice showed decreased gp91phox and p67phox interaction, NADPH oxidase activity, and myocardial oxidative stress in response to angiotensin II (400 ng/kg per day for 2 weeks) stimulation. This result correlated with decreased myocardial hypertrophy. These results indicate that Rac1 is critical for the hypertrophic response in the heart and suggest that therapies which target myocardial Rad may be beneficial in the treatment of cardiac hypertrophy.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - May 9 2006|
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