Abstract 3201: Protein Kinase D1 is Required for Pathological Cardiac Remodeling
The adult heart responds to biomechanical stress and neurohormonal signaling by hypertrophic growth, accompanied by fibrosis and diminished function. Class II histone deacetylases (HDACs) suppress stressdependent remodeling of the heart via their association with the MEF2 transcription factor, an activator of heart disease. Protein kinase D (PKD) is a stress-responsive kinase that phosphorylates class II HDACs, resulting in their dissociation from MEF2 with consequent activation of MEF2 target genes. To further define the functions of PKD1 in the heart, we generated mice with a cardiac-specific mutation of the Prkcm gene (PKD1 cKO). PKD1 cKO mice were indistinguishable from their wild type littermates. When subjected to thoracic aortic constriction (TAC) PKD1 cKO showed less hypertrophy (23% vs 47%, p<0.01) and a reduction in cardiac fibrosis compared to wild type mice. In addition, PKD1 cKO animals were resistant to left ventricular dilation and a decrease in contractility. Upregulation of the hypertrophic gene markers was blunted in mutant mice following TAC. PKD1 is activated by angiotensin II (AngII) in vitro. We therefore examined whether PKD1 was necessary for AngII induced cardiac hypertrophy. Compared to wild type mice PKD1 cKO mice showed a diminished hypertrophic response to AngII (16% vs 11%, p<0.01). There was also a reduction in fibrosis of PKD1 cKO hearts compared to wild type mice. Up-regulation of ANF, a-MHC and Col1a2 expression was also compromised in PKD1 cKO mice. Finally, in contrast to Ang II, isoproterenol (ISO), a beta-adrenergic agonist, does not activate PKD1 in vitro. To examine whether PKD1 is necessary for cardiac hypertrophy in response to beta-adrenergic stimulation we administered isoproterenol to mice. Unexpectedly, we observed that the hearts of PKD1 cKO mice showed less hypertrophy compared wild type mice (21% vs 37%, p<0.01), as well as diminished expression of stress-response genes. Our results demonstrate that PKD1 is a critical component of the signaling pathways through which pressure overload, AngII, and adrenergic signaling drive pathological cardiac remodeling. We conclude that PKD1 functions as a key transducer of stress stimuli involved in pathological cardiac remodeling in vivo.