Does the specific deletion of Rac1 in adult cardiomyocytes prevent angiotensin II-induced oxidative stress and cardiac hypertrophy?
Rac1 is critical for generating oxidative stress and producing cardiac hypertrophy in the adult heart, suggesting it may be a viable therapeutic target for cardiac hypertrophy.
The development of cardiac hypertrophy is mediated, in part, by increase in NADPH oxidase activity and myocardial oxidative stress. The Rho GTPase, Rac, regulates NADPH oxidase activity through interaction with gp91(phox) and p67(phox) (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 Rac1 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 gp91(phox) and p67(phox) 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 Rac1 may be beneficial in the treatment of cardiac hypertrophy.
Satoh et al. (Tue,) studied this question.