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The role of RhoA/ROCK signaling in the development of diabetic cardiomyopathy

University of British Columbia

Diabetic patients have an increased risk of heart failure and sudden death, attributed in part to the development of diabetic cardiomyopathy, defined as ventricular dysfunction independent of hypertension and coronary artery disease. The mechanisms contributing to diabetic cardiomyopathy are not completely understood, but over-activation of the RhoA/ROCK pathway has been identified as a contributor. This research further investigated the roles of cardiomyocyte RhoA and of ROCK2 in the development of diabetic cardiomyopathy. In study one, the effects of heterozygous deletion of ROCK2 (ROCK2+/-) on cardiac function in a CD1 mouse model of type 1 diabetes induced by streptozotocin (STZ) were analyzed, since homozygous ROCK2 deletion is embryonically lethal. Thirteen weeks after diabetes induction, global cardiac function was unchanged in diabetic compared to non-diabetic mice. However, cardiomyocytes isolated from wild-type diabetic mice exhibited arrhythmic Ca²⁺ transients associated with increased ryanodine receptor 2 and CAMKII phosphorylation. These observations were attenuated in ROCK2+/- animals, suggesting that inhibition of ROCK2 may protect against arrhythmogenesis in the diabetic heart. The purpose of study two was to compare the development and progression of cardiac dysfunction in C57BL/6 mice, the strain of mice used in the final study, made diabetic or insulin resistant by dietary intervention and/or STZ treatment. Mice made diabetic with STZ showed the earliest and most severe signs of cardiac dysfunction compared to other models investigated, establishing this as an appropriate model. Given that RhoA is expressed in many different cell types in the heart, the purpose of study three was to analyze the role of cardiomyocyte RhoA in the development of diabetic cardiomyopathy, using mice with inducible cardiac-specific knockdown of RhoA (RhoA-/-). Hearts from diabetic RhoA-/- mice were protected against the development of contractile dysfunction. This was associated with prevention of cardiomyocyte fibrosis, hypertrophy and apoptosis, and with normalization of signaling through the TGF-β pathway, including Smad2 and 3 phosphorylation, and Smad7 expression. Overall, the results demonstrate that deletion of ROCK2 and of cardiomyocyte RhoA protect the diabetic heart. Inhibition of this pathway may be an important therapeutic avenue to decrease the risk of heart failure and sudden death in diabetes.

Text

2019-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64116

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/