ArticleCirculation research2022
Ischemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion Injury.
Article in Circulation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 87 citations in OpenAlex.
- Lactylation: Metabolic epigenetic regulation and cell death mechanisms in myocardial ischemia‒reperfusion injury.Genes & diseases · 2027Review
- Metabolic dependency of malonate protection against cardiac ischemia-reperfusion injury.Basic research in cardiology · 2026Article
- A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.Nature cardiovascular research · 2026Article
- SYVN1-mediated succinate accumulation exacerbates heart failure.Science China. Life sciences · 2026Article
- Brown Adipocyte Sheets Alleviate Myocardial Ischemia-Reperfusion Injury Through NRG4-ErbB4-Dependent Ferroptosis Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitochondrial succinate transport is required for cardiac ischaemia/reperfusion injury.Cardiovascular research · 2026Article
- The role and therapeutic potential of succinate and succinylation in cardiovascular diseases.Clinical epigenetics · 2026Review
- Cell death forms in myocardial ischemia-reperfusion injury and their potential clinical applications.Molecular and cellular biochemistry · 2026Review
- Bimodal regulation and precision therapy of neutrophil extracellular traps in liver ischemia-reperfusion injury: recent advances.Frontiers in immunology · 2026Review
- Protective Effect of Salidroside Against Multiple Organs Ischemia-Reperfusion Injury: New Insights From Common and Specific Pharmacological Mechanisms.Drug design, development and therapy · 2026Review
- Combined machine learning identification and experimental validation of NDUFS8 and SUCLG1 as potential biomarkers for mechanical asphyxia.Frontiers in medicine · 2026Article
- The immune-cardiovascular metabolic circuitry in myocardial ischemia-reperfusion injury: from metabolic signal release to spatiotemporal reprogramming.Frontiers in immunology · 2026Review
- Integrating Senescence and Oxidative Stress in Cardiac Disease.International journal of molecular sciences · 2025Review
- Simultaneous and sensitive quantification of protein and low molecular weight persulfides, polysulfides and HNature communications · 2025Article
- Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.Nature cardiovascular research · 2025Article
- Innovative Application of a Multifunctional Sucrose-Gelatin Hydrogel Matrix in Desorption Electrospray Ionization-Mass Spectrometry Imaging.Analytical chemistry · 2025Article
- Circular RNA circDhx32 promotes cardiac inflammatory responses in mouse cardiac ischemia-reperfusion injury via binding to FOXO1 competed with AdipoR1.Acta pharmacologica Sinica · 2025Article
- Lung Ischemia-Reperfusion Injury in Lung Transplant Surgery: Where Do We Stand?Antioxidants (Basel, Switzerland) · 2025Review
- Roles of Autophagy and Oxidative Stress in Cardiovascular Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Immunometabolism in heart failure.Nature reviews. Cardiology · 2025Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 10 institutions in 7 countries.
Funding
Abstract
backgroundInhibiting 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.
methodsC57BL/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.
resultsMalonate 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.
conclusionsCardioprotection 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.
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