The G-protein-coupled receptors (GPCRs) family of proteins play essential roles in the heart, including in the regulation of cardiac hypertrophy. One member of this family, the oxoglutarate receptor 1 (OXGR1), may have a crucial role in the heart because it acts as a receptor for α-ketoglutarate, a metabolite that is elevated in heart failure patients. OXGR1 is expressed in the heart but its precise function during cardiac pathophysiological process is unknown. Here we used both in vivo and in vitro approaches to investigate the role of OXGR1 in cardiac hypertrophy.Genetic ablation of Oxgr1 in mice (OXGR1−/−) resulted in a significant increase in hypertrophy following transverse aortic constriction (TAC). This was accompanied by reduction in contractile function as indicated by cardiac fractional shortening and ejection fraction. Conversely, adenoviral mediated overexpression of OXGR1 in neonatal rat cardiomyocytes significantly reduced phenylephrine-induced cardiomyocyte hypertrophy, a result that was consistent with the in vivo data. Using a combination of yeast two hybrid screening and phospho-antibody array analysis we identified novel interacting partner and downstream signalling pathway that might be regulated by the OXGR1. First, we found that OXGR1 forms a molecular complex with the COP9 signalosome complex subunit 5 (CSN5). Secondly, we observed that the STAT3 signalling pathway was upregulated in OXGR1−/− hearts. Since CSN5 interacts with TYK2, a major upstream regulator of STAT3, OXGR1 might regulate the pro-hypertrophic STAT3 pathway via interaction with the CSN5-TYK2 complex.In conclusion, our study has identified OXGR1 as a novel regulator of pathological hypertrophy via the regulation of the STAT3. Identification of molecules that can specifically activate or inhibit this receptor may be very useful in the development of novel therapeutic approach for pathological cardiac hypertrophy.

Introduction GPR99, a member of G-protein coupled receptor family, is expressed in the heart. Previous studies suggested that this receptor can bind to alpha-ketoglutarate, a metabolite that is elevated in the serum of heart failure (HF) patients. However, the functional role of GPR99 in cardiomyocytes is unknown. In this study, we investigated whether GPR99 regulates cardiac hypertrophy, a key process in the development of HF. Results Mice with genetic ablation of GPR99 (GPR99-/-) displayed an increased in hypertrophy following transverse aortic constriction (TAC) as indicated by heart weight/body weight ratio. Furthermore, GPR99-/- mice showed significantly increased interstitial fibrosis and larger cell surface area compared to wildtype controls. The cardiac function as indicated by fractional shorting (FS) is significantly lower in the knockout mice compared to wildtype mice following TAC. To examine the mechanism we performed yeast two hybrid screening analysis and have identified CSN5, a member of the COP9 signalosome complex, as a novel interacting partner of the GPR99 receptor. COP9 is known as a regulator of protein degradation via the ubiquitin proteasome system. Adenoviral mediated overexpression of GPR99 in cardiomyocytes induced the ubiquitination and degradation of a prohypertrophic factor interferon regulatory factor 5 (IRF5). Consistently, in GPR99-/- mice expression of IRF5 was significantly increased following TAC, which might provide the possible mechanism responsible for the increased hypertrophy in these mice. Conclusion Our findings suggest that the alpha-ketoglutarate receptor GPR99 modulates pathological hypertrophic response by modulating ubiquitination of IRF5. Thus, GPR99 may become the possible target for heart failure treatment.