Requirement of Rac1 in the development of 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
Minoru
M
Cardiovascular and Hematology Divisions, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ogita
Hisakazu
H
Takeshita
Kyosuke
K
Mukai
Yasushi
Y
Kwiatkowski
David J
DJ
Liao
James K
JK
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D017353:Gene Deletion; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; D048848:MAP Kinase Kinase Kinase 5; D020830:rac1 GTP-Binding Protein