Aminooxyacetic acid attenuates post‐infarct cardiac dysfunction by balancing macrophage polarization through modulating macrophage metabolism in mice. Issue 4 (13th January 2020)

• Record Type: Journal Article
• Authors: Zhao, Pei; Zhou, Wenjing; Zhang, Yanxia; Li, Jingjing; Zhao, Ye; Pan, Lihua; Shen, Zhenya; Chen, Weiqian; Hui, Jie
• Is Part Of: Journal of cellular and molecular medicine. Volume 24:Issue 4(2020)
• Page Start: 2593
• Page End: 2609
• Publication Date: 2020-01-13
• Subjects: aminooxyacetic acid -- macrophage polarization -- metabolic reprogramming -- myocardial infarction -- NLRP3; Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.14972
• Languages: English
• ISSNs: 1582-1838

Abstract

Abstract: Excessive activation of pro‐inflammatory M1 macrophages following acute myocardial infarction (MI) aggravates adverse cardiac remodelling and heart dysfunction. There are two break points in the tricarboxylic acid cycle of M1 macrophages, and aspartate‐arginosuccinate shunt compensates them. Aminooxyacetic acid (AOAA) is an inhibitor of aspartate aminotransferase in the aspartate‐arginosuccinate shunt. Previous studies showed that manipulating macrophage metabolism may control macrophage polarization and inflammatory response. In this study, we aimed to clarify the effects of AOAA on macrophage metabolism and polarization and heart function after MI. In vitro, AOAA inhibited lactic acid and glycolysis and enhanced ATP levels in classically activated M1 macrophages. Besides, AOAA restrained pro‐inflammatory M1 macrophages and promoted anti‐inflammatory M2 phenotype. In vivo, MI mice were treated with AOAA or saline for three consecutive days. Remarkably, AOAA administration effectively inhibited the proportion of M1 macrophages and boosted M2‐like phenotype, which subsequently attenuated infarct size as well as improved post‐MI cardiac function. Additionally, AOAA attenuated NLRP3‐Caspase1/IL‐1β activation and decreased the release of IL‐6 and TNF‐α pro‐inflammatory cytokines and reciprocally increased IL‐10 anti‐inflammatory cytokine level in both ischaemic myocardium and M1 macrophages. In conclusion, short‐term AOAA treatment significantly improves cardiac function in mice with MI by balancing macrophage polarization through modulating macrophage metabolism and inhibiting NLRP3‐Caspase1/IL‐1β pathway.