Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes.
OBJECTIVE
Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes.


METHODS
Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose.


RESULTS
In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose-induced ER stress was inhibited by blocking Rac1 or NADPH oxidase.


CONCLUSIONS
Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy.
Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
Jianmin
J
Li
Huaqing
H
Zhu
E
E
Shen
Li
L
Wan
J Malcolm O
JM
Arnold
Tianqing
T
Peng
D000818:Animals; D017209:Apoptosis; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D006321:Heart / Q000503:physiopathology; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency*; D020257:Ventricular Remodeling / Q000235:genetics*; D020744:rac GTP-Binding Proteins / Q000172:deficiency*; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D003094:Collagen; D019255:NADPH Oxidases; C045073:Cre recombinase; D019426:Integrases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein