Ischemia-selective cardioprotection by malonate for ischemia/reperfusion injury

Prag, H. A. et al. (2022) Ischemia-selective cardioprotection by malonate for ischemia/reperfusion injury. Circulation Research, 131(6), pp. 528-541. (doi: 10.1161/CIRCRESAHA.121.320717) (PMID:35959683) (PMCID:PMC9426742)

Abstract

Background: Inhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to the clinic is understanding the mechanism of malonate entry into cells to enable inhibition of SDH, its mitochondrial target, as malonate itself poorly permeates cellular membranes. The possibility of malonate selectively entering the at-risk heart tissue on reperfusion, however, remains unexplored. Methods: C57BL/6J mice, C2C12 and H9c2 myoblasts, and HeLa cells were used to elucidate the mechanism of selective malonate uptake into the ischemic heart upon reperfusion. Cells were treated with malonate while varying pH or together with transport inhibitors. Mouse hearts were either perfused ex vivo (Langendorff) or subjected to in vivo left anterior descending coronary artery ligation as models of ischemia/reperfusion injury. Succinate and malonate levels were assessed by LC-MS/MS, in vivo by mass spectrometry imaging, and infarct size by TTC staining. Results: Malonate was robustly protective against cardiac ischemia/reperfusion injury, but only if administered at reperfusion and not when infused before ischemia. The extent of malonate uptake into the heart was proportional to the duration of ischemia. Malonate entry into cardiomyocytes in vivo and in vitro was dramatically increased at the low pH (≈6.5) associated with ischemia. This increased uptake of malonate was blocked by selective inhibition of MCT1 (monocarboxylate transporter 1). Reperfusion of the ischemic heart region with malonate led to selective SDH inhibition in the at-risk region. Acid-formulation greatly enhances the cardioprotective potency of malonate. Conclusions: Cardioprotection by malonate is dependent on its entry into cardiomyocytes. This is facilitated by the local decrease in pH that occurs during ischemia, leading to its selective uptake upon reperfusion into the at-risk tissue, via MCT1. Thus, malonate’s preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia/reperfusion injury.

• Item Type: Articles
• Additional Information: This work was supported by the British Heart Foundation (PG/20/10025 to T. Krieg); the Medical Research Council (MC_UU_00015/3 to M.P. Murphy and MR/P000320/1 to T. Krieg), the Wellcome Trust (220257/Z/20/Z to M.P. Murphy, 221604/Z/20/Z to D. Aksentijevic), Barts Charity (MRC0215 to D. Aksentijevic).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Goodwin, Dr Richard
• Authors: Prag, H. A., Aksentijevic, D., Dannhorn, A., Giles, A. V., Mulvey, J. F., Sauchanka, O., Du, L., Bates, G., Reinhold, J., Kula-Alwar, D., Xu, Z., Pellerin, L., Goodwin, R. J.A., Murphy, M. P., and Krieg, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Circulation Research
• Publisher: American Heart Association
• ISSN: 0009-7330
• ISSN (Online): 1524-4571
• Published Online: 12 August 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Circulation Research 131(6): 528-541
• Publisher Policy: Reproduced under a Creative Commons License