Type III Transforming Growth Factor-ß Receptor Drives Cardiac Hypertrophy Through ß-Arrestin2-Dependent Activation of Calmodulin-Dependent Protein Kinase II.

ABSTRACT

The role of type III transforming growth factor-ß receptor (TßRIII) in the pathogenesis of heart diseases remains largely unclear. Here, we investigated the functional role and molecular mechanisms of TßRIII in the development of myocardial hypertrophy. Western blot and quantitative real time-polymerase chain reaction analyses revealed that the expression of TßRIII was significantly elevated in human cardiac hypertrophic samples. Consistently, TßRIII expression was substantially increased in transverse aortic constriction (TAC)- and isoproterenol-induced mouse cardiac hypertrophy in vivo and in isoproterenol-induced cardiomyocyte hypertrophy in vitro. Overexpression of TßRIII resulted in cardiomyocyte hypertrophy, whereas isoproterenol-induced cardiomyocyte hypertrophy was greatly attenuated by knockdown of TßRIII in vitro. Cardiac-specific transgenic expression of TßRIII independently led to cardiac hypertrophy in mice, which was further aggravated by isoproterenol and TAC treatment. Cardiac contractile function of the mice was not altered in TßRIII transgenic mice; however, TAC led to significantly decreased cardiac contractile function in TßRIII transgenic mice compared with control mice. Conversely, isoproterenol- and TAC-induced cardiac hypertrophy and TAC-induced cardiac contractile function impairment were partially reversed by suppression of TßRIII in vivo. Our data suggest that TßRIII mediates stress-induced cardiac hypertrophy through activation of Ca(2+)/calmodulin-dependent protein kinase II, which requires a physical interaction of ß-arrestin2 with both TßRIII and calmodulin-dependent protein kinase II. Our findings indicate that stress-induced increase in TßRIII expression results in cardiac hypertrophy through ß-arrestin2-dependent activation of calmodulin-dependent protein kinase II and that transforming growth factor-ß and ß-adrenergic receptor signaling are not involved in spontaneous cardiac hypertrophy in cardiac-specific transgenic expression of TßRIII mice. Our findings may provide a novel target for control of myocardial hypertrophy.