Omede Ameh, Zi Min, Prehar Sukhpal, Maqsood Arfa, Stafford Nicholas, Mamas Mamas, Cartwright Elizabeth, Oceandy Delvac
Division of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester, M13 9PT, UK.
Keele Cardiovascular Research Group, Institute of Science and Technology in Medicine, Keele University, Stoke-on-Trent, UK.
Biochem Biophys Res Commun. 2016 Oct 28;479(4):708-714. doi: 10.1016/j.bbrc.2016.09.147. Epub 2016 Sep 29.
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.
G蛋白偶联受体（GPCRs）家族蛋白在心脏中发挥着重要作用，包括对心肌肥大的调节。该家族的一个成员，α-酮戊二酸受体1（OXGR1），可能在心脏中起关键作用，因为它作为α-酮戊二酸的受体，α-酮戊二酸是一种在心力衰竭患者中水平升高的代谢物。OXGR1在心脏中表达，但其在心脏病理生理过程中的精确功能尚不清楚。在这里，我们使用体内和体外方法来研究OXGR1在心肌肥大中的作用。小鼠中Oxgr1基因敲除（OXGR1）导致主动脉缩窄（TAC）后肥大显著增加。这伴随着收缩功能的降低，如心脏缩短分数和射血分数所示。相反，腺病毒介导的新生大鼠心肌细胞中OXGR1过表达显著降低了去甲肾上腺素诱导的心肌细胞肥大，这一结果与体内数据一致。通过结合酵母双杂交筛选和磷酸化抗体阵列分析，我们鉴定了可能受OXGR1调节的新型相互作用伙伴和下游信号通路。首先，我们发现OXGR1与COP9信号体复合物亚基5（CSN5）形成分子复合物。其次，我们观察到STAT3信号通路在OXGR1心脏中上调。由于CSN5与STAT3的主要上游调节因子TYK2相互作用，OXGR1可能通过与CSN5-TYK2复合物相互作用来调节促肥大的STAT3通路。总之，我们的研究已将OXGR1鉴定为通过调节STAT3来调节病理性肥大的新型调节因子。鉴定能够特异性激活或抑制该受体的分子可能对开发病理性心肌肥大的新型治疗方法非常有用。
