Objective: The purpose of the present study was to determine whether increased activation of the RhoA/Rho-kinase (ROCK) pathway occurs in diabetic cardiomyopathy and whether acute inhibition of this pathway improves contractile function of the diabetic heart. Methods: Male Wistar rats were made diabetic with streptozotocin. Twelve to fourteen weeks later, the effects of acute administration of the ROCK inhibitors Y-27632 and H-1152 on cardiac contractile function were measured both in vitro, in isolated working hearts, and in vivo, using echocardiography. Changes in the expression and activity of RhoA, and the effect of ROCK inhibition on changes in the phosphorylation of the downstream target of ROCK, LIM kinase 2, and on actin polymerization in diabetic hearts were also determined. Results: Perfusion of isolated working hearts from diabetic rats with Y-27632 or H-1152 acutely improved left ventricle developed pressure and the rates of contraction and relaxation. Acute administration of H-1152 also significantly improved the percent fraction shortening, an index of left ventricle contractility, in vivo in diabetic rats. The expression and activity of RhoA in cardiomyocytes from diabetic rats were significantly increased, as was the phosphorylation of LIM kinase 2. This was associated with an increase in actin polymerization (the F-actin to G-actin ratio). Both the increase in LIM kinase 2 phosphorylation and actin polymerization were attenuated by ROCK inhibition. Conclusions: These data suggest that activation of the RhoA/ROCK signaling pathway plays a critical role in the development of diabetic cardiomyopathy, and that ROCK is an excellent therapeutic target in the treatment of this condition.

These data suggest that iNOS is involved in the increased expression of RhoA in diabetic hearts and that one of the mechanisms by which iNOS inhibition improves cardiac function is by preventing the upregulation of RhoA and its availability for activation.

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