Abstract

Objective. Hyperglycemia induces reactive oxygen species (ROS) and apoptosis in cardiomyocytes, which contributes to diabetic cardiomyopathy. The present study was to investigate the role of Rac1 in ROS production and cardiomyocyte apoptosis during hyperglycemia.

Research Design and Methods. Mice with cardiomyocyte specific Rac1 knockout (Rac1-ko) were generated. Hyperglycemia was induced in Rac1-ko mice and their wild-type littermates by injection of streptozotocin (STZ). In cultured adult rat cardiomyocytes, apoptosis was induced by high glucose.

Results. In a mouse model of STZ-induced diabetes, seven days of hyperglycemia up-regulated Rac1 and NADPH oxidase activation, elevated ROS production and induced apoptosis in the heart. These effects of hyperglycemia were significantly decreased in Rac1-ko mice or wild-type mice treated with apocynin. Interestingly, deficiency of Rac1 or apocynin treatment significantly reduced hyperglycemia-induced mitochondrial ROS production in the heart. Deficiency of Rac1 also attenuated myocardial dysfunction after 2 months of STZ injection. In cultured cardiomyocytes, high glucose up-regulated Rac1 and NADPH oxidase activity and induced apoptotic cell death, which were blocked by over-expression of a dominant negative mutant of Rac1, knockdown of gp91^phox or p47^phox, or NADPH oxidase inhibitor. In type-2 diabetic db/db mice, administration of Rac1 inhibitor, NSC23766 significantly inhibited NADPH oxidase activity and apoptosis, and slightly improved myocardial function.

Conclusions. Rac1 is pivotal in hyperglycemia-induced apoptosis in cardiomyocytes. The role of Rac1 is mediated through NADPH oxidase activation and associated with mitochondrial ROS generation. Our study suggests that Rac1 may serve as a potential therapeutic target for cardiac complications of diabetes.