Cited by 89Cardiac Ischemia and ReperfusionAcute Myocardial Infarction ResearchCardiac Imaging and Diagnostics

Selective Inhibition of Succinate Dehydrogenase in Reperfused Myocardium with Intracoronary Malonate Reduces Infarct Size

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Valls-Lacalle, Laura, Barba, Ignasi, Miró-Casas, Elisabet, Ruiz-Meana, Marisol, Rodríguez-Sinovas, Antonio, García-Dorado, David·2018·Scientific Reports

Abstract

Inhibition of succinate dehydrogenase (SDH) with malonate during reperfusion reduces infarct size in isolated mice hearts submitted to global ischemia. However, malonate has toxic effects that preclude its systemic administration in animals. Here we investigated the effect of intracoronary malonate on infarct size in pigs submitted to transient coronary occlusion. Under baseline conditions, 50 mmol/L of intracoronary disodium malonate, but not lower concentrations, transiently reduced systolic segment shortening in the region perfused by the left anterior descending coronary artery (LAD) in open-chest pigs. To assess the effects of SDH inhibition on reperfusion injury, saline or malonate 10 mmol/L were selectively infused into the area at risk in 38 animals submitted to ischemia-reperfusion. Malonate improved systolic shortening in the area at risk two hours after 15 min of ischemia (0.18 ± 0.07 vs 0.00 ± 0.01 a.u., p = 0.025, n = 3). In animals submitted to 40 min of ischemia, malonate reduced reactive oxygen species production (MitoSOX staining) during initial reperfusion and limited infarct size (36.46 ± 5.35 vs 59.62 ± 4.00%, p = 0.002, n = 11), without modifying reperfusion arrhythmias. In conclusion, inhibition of SDH with intracoronary malonate during early reperfusion limits reperfusion injury and infarct size in pigs submitted to transient coronary occlusion without modifying reperfusion arrhythmias or contractile function in distant myocardium.

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  • Nuclear FH generates fumarate via its reverse activity, which inhibits KDM2B and facilitates binding of DNA repair proteins.

    “Here, via its reverse activity, it generates fumarate that inhibits histone lysine demethylase KDM2B, which in turn facilitates the binding of proteins involved in DNA repair177.”
  • Upon DNA damage, FH localises in the nucleus where it is phosphorylated by DNA-PKcs.

    “Upon DNA damage, FH localises in the nucleus, where it is phosphorylated by the catalytic subunit of DNA-PK (DNA-PKcs)177.”

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Authors
Valls-Lacalle, L., Barba, I., Miró-Casas, E., Ruiz-Meana, M., Rodríguez-Sinovas, A., & García-Dorado, D.
Affiliations
Universitat Autònoma de Barcelona (ES)
Venue
Scientific Reports
Published
2018-02-05
Volume
8
Issue
1
Pages
2442-2442
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2807458340
Cited by
88
References
38
Citations by year
2026: 9 · 2025: 9 · 2024: 9 · 2023: 14 · 2022: 10 · 2021: 17 · 2020: 10 · 2019: 7 · 2018: 3
FWCI
7.04
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ministerio de Economía y Competitividad (PI14/, RD12/0042/0021)
  • Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares
  • Instituto de Salud Carlos III (RD12-00420021, PI14/, PI17/01397, PI14/01431 and PI17/01397, RD12/0042, PI14/01431)
  • European Regional Development Fund (PI17/01397, RD12/0042)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
Keywords
succinate dehydrogenase inhibition, malonate, myocardial ischemia-reperfusion injury, infarct size, transient coronary occlusion, ischemia-reperfusion, reactive oxygen species, MitoSOX, reperfusion arrhythmias, cardiac contractility, intracoronary drug delivery, porcine model
MeSH terms
Animals, Cardiotonic Agents, Coronary Circulation, Coronary Vessels, Heart Rate, Hemodynamics, Injections, Intravenous, Malonates, Myocardial Infarction, Myocardium, Succinate Dehydrogenase, Swine, Myocardial Reperfusion Injury, Arterial Pressure

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