Abstract 19161: cAMP Regulated Transcriptional Coactivator 1 - A Novel Player in Cardiac Hypertrophy

Abstract

Maladaptive cardiac hypertrophy leads to heart failure, a common cause for hospitalization. Chronic β-adrenergic, PKA dependent signaling and calcineurin contribute to hypertrophy. These signals converge in many tissues on the cAMP Regulated Transcriptional Coactivator 1 (CRTC1). We studied if CRTC1 promotes the development of maladaptive cardiac hypertrophy in human and murine hearts. In cardiomyocytes, treatment with β-adrenoceptor agonist isoprenaline dephosphorylated, thus activated 59 ± 5 % of total CRTC1, as seen by immunoblot (n = 3-4). Activation was prevented by propranolol. CRTC1 was not activated by endothelin or angiotensin II. CRTC1 protein content was enhanced in human and murine heart tissue under conditions of acquired and inherited maladaptive hypertrophy, seen by immunoblot (n = 7-8). Crtc1 -deficient mice (KO) showed a higher ratio of heart weight to tibia length than their wild-type littermates (WT) (8.6 ± 0.4 mg/mm vs. 10.9 ± 0.8 mg/mm in WT and KO, respectively, n = 12) and increased myocyte size (516 ± 8 μm 2 vs. 590 ± 11 μm 2 in WT and KO, respectively, n = 3 hearts). Echocardiographically assessed, the ejection fraction, fractional area shortening and cardiac output were reduced by 47 ± 8 %, 49 ± 12 % and 42 ± 9 %, respectively, in KO mice (n = 6-9). mRNA levels of Nppa , Nppb , Acta1 , Myh7 and the pro-fibrotic Ctgf did not differ between WT and KO mice (n = 12-15). By reducing G αq -protein induced signals in the heart, the Regulator of G-Protein Signaling 2 (RGS2) reduces hypertrophy. In KO mice the Rgs2 mRNA and protein levels were reduced by 26 ± 10 % and by 38 ± 8 %, respectively (n = 8-10). In a luciferase reporter gene assay overexpression of CRTC1 stimulated Rgs2 promoter transcriptional activity 1.8 fold (± 0.1); mutation of the CRTC1-interaction site, the cAMP-response element, prevented CRTC1-induced transcriptional activity (n = 6). In addition, chromatin immunoprecipitation showed the recruitment of endogenous CRTC1 to the Rgs2 promoter in cardiac tissue. In conclusion, our data indicate that increased CRTC1 protein content in maladaptive cardiac hypertrophy is a compensatory mechanism to delay disease progression, in part by upregulation of RGS2. Thus, CRTC1 represents a novel player of cardiac hypertrophy.