G-Protein-Coupled Receptor 91-Dependent Signalling Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidaemic Mice

Abstract

The TCA cycle intermediate metabolite ‘succinate’ has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic inflammatory process of atherosclerosis has never been investigated. The examination of publicly available datasets revealed that the SUCNR1 gene is expressed in human atherosclerotic plaques, especially in vascular smooth muscle cells. Using GPR91 knockout (Gpr91−/−) and wildtype (WT) littermates, made hyperlipidaemic with the overexpression of the gain-of-function mutated Pcsk9 and Western diet feeding, we showed that the full ablation of GPR91 did not accelerate atherosclerosis—lesions in the aortic arch 2.18 ± 0.48% vs. 1.64 ± 0.31%, and in the aortic roots 10.06 ± 0.91% vs. 10.67 ± 1.53% for Gpr91−/− and WT mice, respectively. In line with this, no differences between groups were observed for macrophage and T-cell infiltration in the plaque, as well as the polarization towards M1- or M2-like macrophages in the aorta, spleen and liver of Gpr91−/− and WT control mice. In conclusion, our study indicates that the global ablation of GPR91 signalling does not influence vascular inflammation or atherogenesis.

Keywords

• atherosclerosis
• inflammation
• GPR91
• SUCNR1
• succinate
• TCA