Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments

Abstract

Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy.

Figure 1

Multiple sources of reactive oxygen species during reperfusion following myocardial ischemia. These are mainly mitochondria, xanthine oxidoreductase, uncoupled nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, and some other sources. Abbreviations: NADPH: nicotinamide adenine dinucleotide phosphate; NADH: nicotinamide adenine dinucleotide; FADH2: flavin adenine dinucleotide hydrogen transmitter; O₂⁻: superoxide; Cyt: cytochrome; UCP: uncoupled protein; GSH-Px: glutathione peroxidase; XDH: xanthine dehydrogenase; FAD: flavin adenine dinucleotide; FMN: flavin mononucleotide; BH4: tetrahydrobiopterin; MAO: monoamine oxidase; LOX: lipoxygenases; CA: catecholamine; NE: neutrophil; COX: cyclooxygenase; XO: xanthine oxidase.

Figure 2

The damage of oxidative stress to cardiomyocytes during reperfusion. Reactive oxygen species affect Ca²⁺ overload and Bcl-2 family proteins, which lead to the mitochondrial permeability transformation pore opening and ultimately lead to myocardial apoptosis. Reactive oxygen species also trigger exogenous apoptosis by activating the MAPK family. Finally, reactive oxygen species initiate apoptosis through ER stress. Beclin1 and LAMP2, which are regulated by reactive oxygen species, cause impaired autophagy or excessive autophagy, thereby damaging cardiomyocytes. Via inflammatory response, reactive oxygen species induce pathological damage of the heart. NO, one of the members of reactive nitrogen, damages cardiomyocytes through direct cytotoxicity or generates ONOO⁻ with O₂⁻ to cause cardiomyocyte damage. Abbreviations: MAPK: mitogen-activated protein kinase; NF-κB: nuclear transcription factor-κB; TNF-α: tumor necrosis factor-α; TNFR1: tumor necrosis factor receptor 1; Fas: tumor necrosis factor superfamily; CyP-D: cyclophilin D; Bcl-2: B cell lymphoma-2; MPTP: mitochondrial permeability transition pore; AIF: apoptosis-inducing factor; Cyt: cytochrome; LAMP2: lysosomal-associated membrane protein 2; Apaf-1: apoptosis protease-activating factor-1; ONOO⁻: peroxynitrite; NLRP3: nucleotide-binding oligomerization domain-like receptor protein 3; MMPs: matrix metalloproteinases; ER stress: endoplasmic reticulum stress; CHOP: CCAAT/enhancer-binding protein homologous protein.