Abstract 11221: Cardiac-specific Coxsackie and Adenovirus Receptor (CAR) Deletion Attenuates Cardiac Hypertrophy Through AT1 Disruption Induced STAT3 Inactivation
In the adult heart, CAR expression is localized to the intercalated disc and sarcolemma membrane. However, the role of CAR in hypertrophy is unknown. We previously generated cardiac-specific CAR knock out (CAR-cKO) mice, which induced cardiomyopathy at 24 weeks of age with abnormalities in intercalated disc structure. The hearts were not dilated and there was not evidence of myocyte hypertrophy in the cardiomyopathic hearts. Therefore, we hypothesized that hypertrophy induced by pressure overload would be attenuated in the absence of CAR.
The CAR-cKO mice myocytes size is significantly smaller than wild type mice at 10 week old ages. Pressure overload was induced using Transverse aortic constriction (TAC) of 10 week old age mice. 8 day post-TAC, echocardiography was performed. The increase in left ventricular end-systolic wall dimension (LVEDs, 0.81±0.04 vs 0.68±0.02, p<0.05) and left ventricular posterior wall (LVPWd, 0.82±0.04 vs 0.69±0.03, p<0.05; wild type vs CAR-cKO) thickness was attenuated in CAR-cKO hearts compared to wild type mice. In addition, we also observed a decrease in STAT3 phosphorylation in the CAR deficient hearts. Neonatal cardiomyocytes were cultured from CARflox/flox mice and infected with adenovirus-Cre to delete CAR. CAR deletion attenuated STAT3 signal activity by angiotensin II (1μm) treatment. However, expression of constitutively active STAT3 by adenovirus infection rescued the attenuation of single myocytes size decrease from CAR deleted neonatal cardiomyocyte. It confirmed the attenuation of compensatory hypertrophy signal without CAR. In addition, AT1 was decreased in CAR-cKO heart compare to wild type heart.
CAR expression is required for normal hypertrophic signal induction through AT1 receptor regulates STAT3 activation in the ventricular myocyte. This indicates that CAR has an important role the normal compensatory hypertrophy signal regulation and maybe a co-ligand of GPCR protein such as AT1 receptor.
- © 2012 by American Heart Association, Inc.