Myocardial ischemia/reperfusion injury: Mechanisms of injury and implications for management (Review)

Abstract

Myocardial infarction is one of the primary causes of mortality in patients with coronary heart disease worldwide. Early treatment of acute myocardial infarction restores blood supply of ischemic myocardium and decreases the mortality risk. However, when the interrupted myocardial blood supply is recovered within a certain period of time, it causes more serious damage to the original ischemic myocardium; this is known as myocardial ischemia/reperfusion injury (MIRI). The pathophysiological mechanisms leading to MIRI are associated with oxidative stress, intracellular calcium overload, energy metabolism disorder, apoptosis, endoplasmic reticulum stress, autophagy, pyroptosis, necroptosis and ferroptosis. These interplay with one another and directly or indirectly lead to aggravation of the effect. In the past, apoptosis and autophagy have attracted more attention but necroptosis and ferroptosis also serve key roles. However, the mechanism of MIRI has not been fully elucidated. The present study reviews the mechanisms underlying MIRI. Based on current understanding of the pathophysiological mechanisms of MIRI, the association between cell death-associated signaling pathways were elaborated, providing direction for investigation of novel targets in clinical treatment.

Keywords: apoptosis; autophagy; ferroptosis; myocardial ischemia/reperfusion injury; necroptosis; pyroptosis; reactive oxygen species.

Figure 1

During ischemia, cardiomyocytes undergo anaerobic metabolism, which results in decreased ATP levels and pH, which increase levels of intracellular Na⁺ and Ca²⁺. Reperfusion leads to further increases in intracellular Ca²⁺ and ROS, which cause MIRI. The primary apoptosis signaling pathways are the intrinsic (mitochondrial) and extrinsic (death receptor) pathway. The intrinsic pathway is induced by release of CytC, which is regulated by Bcl-2 family proteins. The extrinsic pathway is triggered by death receptors (such as TNFR) that activate caspase-8. Programmed necroptosis is mediated by the complex RIP1-RIP3 and MLKL when caspase-8 is inhibited, but the downstream pathway of MLKL remains unclear. Necroptosis and apoptosis have certain commonalities. For instance, caspase-8 decreases MIRI via inhibiting necroptosis by binding to an anti-apoptotic protein (cFLIP). Three forms of autophagy are macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy is the primary pathway, which is promoted by PI3K, AMPK and Beclin1, while AKT/mTOR pathways inhibit this type of autophagy. Beclin1 is abundant in the ER. However, it remains uncertain whether ERS regulates expression of Beclin1 during ischemia or reperfusion. During ischemia and early reperfusion, cellular acidosis, internal environmental instability and other factors promote the release of ferrivalent or ferrous ions from enzymes, thereby activating the Fenton reaction, resulting in increased ROS, which leads to ferroptosis of cardiomyocytes. ROS, reactive oxygen species; MIRI, myocardial ischemia/reperfusion injury; CytC, cytochrome c; TNFR, tumor necrosis factor receptor; RIPK, receptor-interacting protein kinase; MLKL, mixed lineage kinase domain-like protein; cFLIP, CASP8 and FADD-like apoptosis regulator; AMPK, AMP-activated protein kinase; ERS, endoplasmic reticulum stress; JAK, Janus kinase; GFR, growth factor receptor; FADD, Fas-associated death domain; TRADD, tumor necrosis factor receptor type 1-associated death domain protein; MCU, mitochondrial calcium uniporter; mPTP, mitochondrial permeability transition pore; EPO, erythropoietin; ?, unknown mechanism.