Abstract 10984: Spontaneous Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Mice Overexpressing Dominant-Negative Rho-Kinase in Vascular Smooth Muscle Cells
Background: Rho-kinase is an important regulator of the cytoskeleton, thus playing vital roles in cell motility, contraction, proliferation and apoptosis. We have previously demonstrated that the Rho/Rho-kinase pathway in vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of cardiovascular diseases by accelerating VSMC migration, proliferation, and inflammation. However, the role of Rho-kinase during cardiovascular development has not been fully explored.
Methods and Results: We newly generated transgenic mice overexpressing a dominant-negative Rho-kinase (DN-RhoK) under the control of the SM22α promoter, where Rho-kinase activity was reduced by 27%. On embryonic day (E) 12.5, DN-RhoK hearts revealed marked thinning of the ventricles and interventricular septum (n=38). Cardiomyocyte proliferation was markedly reduced in DN-RhoK embryos hearts. DN-RhoK mice progressively developed dilatation of the right ventricle (RV) and atrium during the first postnatal week (n=20) and showed high mortality rate after the birth (52.5% died by 4 weeks of age, n=36). By the age of 9 weeks, 76.7% of the DN-RhoK mice died suddenly, whereas only 0.5% of littermates died during the same period (n=102 and 220, respectively, P<0.001). Holter ECG demonstrated spontaneous occurrence of ventricular arrhythmias in all DN-RhoK mice (100%) but no arrhythmias in littermates. In addition, PR interval (33.2±1.4 vs. 30.3±1.6 ms; n=5, P<0.05) and QRS duration (15.2±0.9 vs. 12.8±1.5 ms; n=5, P<0.05) were significantly prolonged in DN-RhoK mice compared to littermates. Although body weight was comparable between the two genotypes, RV/body weight ratio was significantly higher in DN-RhoK mice compared to littermates (P<0.05). Importantly, histological examination showed that DN-RhoK mice had marked dilatation, thinning, and fibrosis in the RV. In contrast, transgenic mice overexpressing cardiomyocyte-specific DN-RhoK did not show any cardiac phenotypic abnormalities.
Conclusions: VSMC-specific DN-RhoK mice exhibit distinct phenotypes closely resembling human arrhythmogenic RV cardiomyopathy (ARVC), suggesting the involvement of Rho-kinase pathway abnormality in VSMC (but not in cardiomyocytes) in the pathogenesis of ARVC.
- © 2012 by American Heart Association, Inc.