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. 2021 Mar 22;22(6):3224. doi: 10.3390/ijms22063224

Figure 3.

Figure 3

Mechanisms of cell death after myocardial I/R injury. After hypoxia, myocardial cell death is primarily driven by necrosis subsequent to the loss of mitochondrial function and opening of the mitochondrial permeability transition pore (mPTP). Necrosis also exists as a regulated form of cell death, i.e., necroptosis. Necroptosis is initiated via the activation of death receptors (e.g., tumor necrosis factor receptor 1 (TNFR1). Signaling commences via receptor-interacting protein 1 (RIP1), which mediates the activation of receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) alternative activation of calcium-calmodulin-kinase II (CaMKII) by the RIP3/RIP1/MLKL/FADD complex induces mitochondrial dysfunction and membrane permeabilization via cyclophilin D, VDAC, and ANT. Pyroptosis is associated with inflammation subsequent to the ischemic insult and mediated via the NLRP3-inflammasome, caspase-1, and enhanced cytokine production. Mitochondria related apoptosis can also be elicited via mechanisms culminating in the release of cytochrome c and the formation of the apoptosome. Pharmacologic cardioprotection has been shown to act on all forms of cell death by maintaining mitochondrial function, reducing ROS production, as well as direct inhibition of apoptotic signaling or the activation of pro-survival signaling pathways, respectively. Abbreviations: ANT = adenine nucleotide translocator; Apaf-1 = apoptotic protease activating factor 1; Bax = Bcl-2-associated X protein; CaMKII = calcium-calmodulin-kinase II; DAMPs = damage-associated molecular patterns; FADD = Fas-associated protein with death domain; IL-1β = interleukin-1β; IL-18 = interleukin-18; MLKL = mixed lineage kinase domain-like; NLRP3 = NOD-, LRR-, and pyrin domain-containing protein 3; RIP1 = receptor-interacting protein 1; TNFα = tumor necrosis factor α; TNFR1 = tumor necrosis factor receptor 1; TRAF2 = tumor necrosis factor receptor-associated factor 2; TRADD = tumor necrosis factor receptor type 1-associated DEATH domain; VDAC = voltage-dependent anion-selective channel.