Rho Kinase Inhibition Improves Cardiac Cross‐Bridge Dynamics in Early Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is associated with left ventricle fibrosis, hypertrophy and diastolic dysfunction. Cardiomyocyte subcellular alterations are thought to drive contractile dysfunction in early DCM. Rho kinase (ROCK) has been implicated in the pathogenesis of DCM and is known to interact with proteins in the actin-myosin cross-bridge (CB) that control myosin head extension. With the use of synchrotron radiation, we are able to examine CB dynamics in real time in the in situ beating heart. Thus, we aimed to determine if ROCK was involved in the pathogenesis of DCM. Cardiac CB dynamics and function were examined in control and diabetic rats treated a ROCK inhibitor (fasudil, 10mg/kg/day) or saline vehicle for two weeks, one week after the induction of diabetes. In the deeper subendocardial layer of the myocardium, diabetic rats had significantly reduced diastolic myosin head extension (p<0.05) compared to control rats. Fasudil treatment improved diastolic myosin head extension in the subendocardium of diabetic rats. Impaired CB function was associated with a trend for a 20% reduction in myosin binding protein C expression in diabetic rats compared to control rats, and fasudil treatment partially prevented this reduction in diabetic rats. Our results suggest ROCK may impair CB dynamics in early DCM by altering the phosphorylation of thick filament proteins.