Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study.

Anaïs Moyon,Guillaume Hache,Laure Balasse,Françoise Dignat-George,Philippe Garrigue,David Taïeb,Pauline Brige,Samantha Fernandez,Ahlem Bouhlel,Benjamin Guillet

doi:10.3390/cells10040795

Abstract

Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([68Ga]Ga-RGD2) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.

Highlights

Succinate is an intermediate of the tricarboxylic acid cycle (e.g., Krebs cycle), and is oxidized to fumarate by the succinate dehydrogenase complex (SDH), which belongs to the electron transport chain [1]
Quantitative analysis highlighted a significant overexpression of G-protein-coupled receptor 91 (GPR91) in ischemic muscle compared to contralateral muscle in phosphate buffer saline (PBS)-treated mice and in succinate-treated mice
A significant overexpression of GPR91 was found in ischemic muscles of succinate-treated mice compared to these of PBS-treated mice

Summary

Introduction

Succinate is an intermediate of the tricarboxylic acid cycle (e.g., Krebs cycle), and is oxidized to fumarate by the succinate dehydrogenase complex (SDH), which belongs to the electron transport chain [1]. Beyond its role in carbohydrate metabolism, succinate was found to play an oncometabolite role in SDH-mutated pheochromocytomas and paragangliomas [2]. Succinate has hormone-like actions in various conditions, including malignancies [3]. These effects are related to paracrine effects via an extracellular. G-protein-coupled receptor named succinate receptor 1 (SUCNR1/GPR91) [4]. Cancer promoting effects of succinate-GPR91 signaling have recently been recognized, and include induction of epithelial to mesenchymal transition, migration, and metastatic spread of lung cancer cells as well as immunosuppressive effects [5]. GPR91 is expressed in several tissues such as the spleen, the kidneys, the liver, the placenta, the myocardium, the retina, and the aorta [7,8,9]

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Conclusion