Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.

Autor: Abe J; Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK.; MRC Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK., Vujic A; Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK., Prag HA; Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK. hap38@cam.ac.uk.; MRC Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK. hap38@cam.ac.uk., Murphy MP; Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK. mpm@mrc-mbu.cam.ac.uk.; MRC Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK. mpm@mrc-mbu.cam.ac.uk., Krieg T; Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK. tk382@medschl.cam.ac.uk.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2024 Aug; Vol. 119 (4), pp. 691-697. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1007/s00395-024-01063-z
Abstrakt: The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.
(© 2024. The Author(s).)
Databáze: MEDLINE
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