Abstract 196: Diacylglycerol Kinase-ϵ Prevents Cardiac Hypertrophy And Fibrosis Induced By Aortic Banding: A new specific regulator of Gαq signaling cascade
Background: The Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) catalyzes DAG and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. We previously found that DGKζ inhibited GPCR agonist-induced cardiac hypertrophy. It has been reported that DGKϵ acts specifically on DAG produced by inositol cycling compared to DGKζ, suggesting different function in two DGK isoforms. The purpose of this study was to examine whether DGKϵ modifies cardiac hypertrophy induced by pressure overload.
Methods and Results: Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of DGKϵ (DGKϵ-TG) and wild-type (WT) mice. Increases in heart/body weight ratio after TAC were significantly abolished in DGKϵ-TG mice compared to WT mice. Dilation of the left ventricular cavity and impaired cardiac systolic function after TAC were significantly attenuated in DGKϵ-TG mice compared to WT mice (Figure A⇓). Translocation of PKCα and ϵ isoforms and induction of fetal genes such as ANF and β-MHC were observed after TAC in WT mice, but not in DGKϵ-TG mice. Cardiac fibrosis and up-reglation of profibrotic genes after TAC observed in WT mice were significantly attenuated in DGKϵ-TG mice. The survival rate after TAC was significantly improved in DGKϵ-TG mice compared to WT mice (Figure B⇓).
Conclusion: These results demonstrate the first evidence that DGKϵ blocks cardiac hypertrophy, fibrosis, and decompensated heart failure after TAC in vivo.