{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:02:33Z","timestamp":1793149353708,"version":"4.5.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2022,9,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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 liquid chromatography-tandem mass spectrometry LC-MS\/MS, in vivo by mass spectrometry imaging, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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 (\u22486.5) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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\u2019s preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia\/reperfusion injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.121.320717","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T05:00:40Z","timestamp":1660280440000},"page":"528-541","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":106,"title":["Ischemia-Selective Cardioprotection by Malonate for Ischemia\/Reperfusion Injury"],"prefix":"10.1161","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4753-8567","authenticated-orcid":true,"given":"Hiran A.","family":"Prag","sequence":"first","affiliation":[{"name":"Department of Medicine (H.A.P., A.V.G., J.F.M., O.S., D.K.-A., M.P.M., T.K.), University of Cambridge, United Kingdom."},{"name":"MRC Mitochondrial Biology Unit (H.A.P., A.V.G., G.B., J.R., M.M.P.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunja","family":"Aksentijevic","sequence":"additional","affiliation":[{"name":"Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (D.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1087-4057","authenticated-orcid":true,"given":"Andreas","family":"Dannhorn","sequence":"additional","affiliation":[{"name":"Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R&amp;D, AstraZeneca, Cambridge, United Kingdom (A.D., R.J.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail V.","family":"Giles","sequence":"additional","affiliation":[{"name":"Department of Medicine (H.A.P., A.V.G., J.F.M., O.S., D.K.-A., M.P.M., T.K.), University of Cambridge, United Kingdom."},{"name":"MRC Mitochondrial Biology Unit (H.A.P., A.V.G., G.B., J.R., M.M.P.), University of Cambridge, United Kingdom."},{"name":"Laboratory of Cardiac Energetics, National Heart, Lung and Blood Institute, Bethesda, MD (A.V.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3843-2442","authenticated-orcid":true,"given":"John F.","family":"Mulvey","sequence":"additional","affiliation":[{"name":"Department of Medicine (H.A.P., A.V.G., J.F.M., O.S., D.K.-A., M.P.M., T.K.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Sauchanka","sequence":"additional","affiliation":[{"name":"Department of Medicine (H.A.P., A.V.G., J.F.M., O.S., D.K.-A., M.P.M., T.K.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luping","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Tianjin Medical University, China (L.D., Z.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6574-5164","authenticated-orcid":true,"given":"Georgina","family":"Bates","sequence":"additional","affiliation":[{"name":"MRC Mitochondrial Biology Unit (H.A.P., A.V.G., G.B., J.R., M.M.P.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Reinhold","sequence":"additional","affiliation":[{"name":"MRC Mitochondrial Biology Unit (H.A.P., A.V.G., G.B., J.R., M.M.P.), University of Cambridge, United Kingdom."},{"name":"Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park (J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duvaraka","family":"Kula-Alwar","sequence":"additional","affiliation":[{"name":"Department of Medicine (H.A.P., A.V.G., J.F.M., O.S., D.K.-A., M.P.M., T.K.), University of Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhelong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Tianjin Medical University, China (L.D., Z.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Pellerin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Physiologie, Universit\u00e9 de Lausanne, Switzerland (L.P.)."},{"name":"Centre de R\u00e9sonance Magn\u00e9tique des Syst\u00e8mes Biologiques, UMR5536 CNRS, LabEx TRAIL-IBIO, Universit\u00e9 de Bordeaux, France (L.P.)."},{"name":"Inserm U1313, Universit\u00e9 et CHU de Poitiers, France (L.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. 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