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.
Basic Res Cardiol. 2024 Aug;119(4):691-697. doi: 10.1007/s00395-024-01063-z. Epub 2024 Jun 12.
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.
琥珀酸是一种关键的线粒体代谢物，是缺血/再灌注损伤（IRI）的驱动因素。在再灌注时，使用丙二酸盐抑制琥珀酸脱氢酶（SDH）是一种有效的治疗策略，可以在小鼠和猪体内的心肌梗死（MI）模型中实现短期（<24 小时再灌注）的心脏保护。我们旨在评估在再灌注时给予丙二酸盐以抑制 IRI 是否可以预防 28 天后的梗死后心力衰竭（HF）。雄性 C57BL/6J 小鼠接受 30 分钟的左前冠状动脉（LAD）闭塞，然后进行 28 天的再灌注。在再灌注时给予丙二酸盐或无丙二酸盐对照作为单次剂量。通过超声心动图评估心功能，通过 Masson 三色染色评估纤维化。无丙二酸盐的再灌注显著降低了射血分数（47%）、缩短分数（23%），并在梗死后 28 天增加了胶原沉积。丙二酸盐作为单次输注（10 分钟内 16mg/kg/min）在再灌注时给予，具有显著的心脏保护作用，保留了射血分数（60%）和缩短分数（30%），并且胶原沉积较少。使用酸化的丙二酸盐制剂，通过单羧酸转运蛋白 1 增强其进入心肌细胞的摄取，1.6 和 16mg/kg/min 10 分钟输注均导致梗死后长期心脏保护作用，保留了射血分数（>60%）和缩短分数（~30%），并且胶原沉积明显少于对照心脏。在再灌注时给予丙二酸盐可预防梗死后 HF。丙二酸盐的酸化使较低剂量的丙二酸盐也能在梗死后实现长期心脏保护。因此，在再灌注时给予酸化的丙二酸盐是一种有前途的治疗策略，可以预防 IRI 和梗死后 HF。
