177 The Alpha-ketoglutarate Receptor GPR99 Regulates Pathological Cardiac Hypertrophy

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Abstract

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.

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