Crosstalk among Reactive Oxygen Species, Autophagy and Metabolism in Myocardial Ischemia and Reperfusion Stages

Abstract

Myocardial ischemia is the most common cardiovascular disease. Reperfusion, an important myocardial ischemia tool, causes unexpected and irreversible damage to cardiomyocytes, resulting in myocardial ischemia/reperfusion (MI/R) injury. Upon stress, especially oxidative stress induced by reactive oxygen species (ROS), autophagy, which degrades the intracellular energy storage to produce metabolites that are recycled into metabolic pathways to buffer metabolic stress, is initiated during myocardial ischemia and MI/R injury. Excellent cardioprotective effects of autophagy regulators against MI and MI/R have been reported. Reversing disordered cardiac metabolism induced by ROS also exhibits cardioprotective action in patients with myocardial ischemia. Herein, we review current knowledge on the crosstalk between ROS, cardiac autophagy, and metabolism in myocardial ischemia and MI/R. Finally, we discuss the possible regulators of autophagy and metabolism that can be exploited to harness the therapeutic potential of cardiac metabolism and autophagy in the diagnosis and treatment of myocardial ischemia and MI/R.

Figure 1.

Overview of autophagy. Three broad types of autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy.

Figure 2.

Metabolic regulatory network of ROS-related autophagic flux. Ac-CoA: acetyl-CoA; AMPK: 5’ AMP-activated protein kinase; AL/ML: autolysosome/mitolysosome; AP/MP: autophagosome/mitophagosome; ATs: acetyltransferases; BCAA: branched chain amino acids; LS: lysosome; mTORC1: mechanistic target of rapamycin complex 1.

Figure 3.

Summary of altered metabolic pathways in ROS-related autophagic flux during MI and MI/R injury based on metabolomics. α-KG: α-ketoglutarate; Ac-CoA: acetyl-CoA; BCAA: branched chain amino acid; BCKA: branched-chain keto acids; FFA: free fatty acids; GLS: glutaminase; GLUT: glucose transporter; HK: hexokinase; LDH: lactate dehydrogenase; NO: nitric oxide; NOS: nitric oxide synthase; PEP: phosphoenolpyruvate; PKM2: pyruvate kinase isozyme type M2.

Figure 4.

Overview of mitophagy. Summary of the three regulatory pathways of mitophagy: PINK1-mediated, BNIP3- and BNIP3L-mediated, and ATAD3B-mediated pathways.

Figure 5.

Workflow of metabolomics. Metabolomics analysis included biofluid collection and preparation, metabolomic data acquisition, acquired data annotation, metabolomic pathway annotation, metabolomic network annotation, and functional validation.