Abstract 12399: The G-Protein Coupled Receptor 99 (gpr99), a Receptor for Heart Failure Metabolite Alpha-Ketoglutarate, Regulates Pressure Overload Induced Hypertrophy in Mice
Members of the G-protein-coupled receptors (GPCRs) family have been known to play important roles in pathological conditions including cardiac hypertrophy. However the role of GPR99, a member of the GPCR protein family, in the heart is unknown. GPR99 is expressed in the heart and its role during cardiac pathophysiological processes may be crucial because it acts as a receptor for [[Unable to Display Character: ɑ]]lpha-ketoglutarate, a metabolite that is elevated in heart failure patients. Here we used both in vivo and in vitro approaches to investigate the role of GPR99 during cardiac hypertrophy. Genetic ablation of GPR99 in mice (GPR99-/-) resulted in a marked increased in hypertrophy following two weeks transverse aortic constriction (TAC), as indicated by heart weight/tibia length ratio (HW/TL: GPR99-/- TAC: 7.9±0.31mg/mm; WT-TAC: 7.1±0.24 mg/mm; Mean ± SEM; n=6&7 ;P<0.05). Moreover, interstitial fibrosis was increased by 11.8 % and fractional shortening was reduced by 11.3 % in GPR99-/- TAC mice compared to wild type (WT) controls. Using a combination of microarray and yeast two hybrid screening analyses we identified two novel signaling pathways downstream of the GPR99 receptor. First, we found that GPR99 forms a molecular complex with TYK2, an upstream regulator of pro-hypertrophic factors, STAT1 and STAT3. Adenoviral mediated overexpression of GPR99 in neonatal rat cardiomyocytes significantly reduced TYK2 and STAT1/3 phosphorylation. Conversely, this pathway was over-activated in GPR99-/- mice following TAC. Secondly, we found that through interaction with CSN5, GPR99 regulates the ubiquitination of Interferon Regulatory Factor 5 (IRF5) and IRF8, which are known as pro-hypertrophic factors. Overexpression of GPR99 enhanced ubiquitination of both IRF5 and IRF8 whereas deletion of this receptor reduced IRF5/8 ubiquitination. In conclusion, our data suggest that GPR99 modulates the pathological hypertrophic response possibly by regulating the STAT pathway and the ubiquitination of IRFs. This study may open a new insight into the possibility of targeting this receptor for future therapeutical approach.
Author Disclosures: A. Omede: None. M. Zi: None. S. Prehar: None. A. Maqsood: None. E. Cartwright: None. M. mamas: None. D. Oceandy: None.
- © 2014 by American Heart Association, Inc.