Table 1 Cell death patterns in myocardial I/R injury.
From: Different types of cell death and their interactions in myocardial ischemia–reperfusion injury
Cell death | In myocardial I/R injury | Activating molecules | Key regulatory factors | Reference |
|---|---|---|---|---|
Apoptosis | During the myocardial ischemia period, the process of apoptosis proceeds slowly. In the reperfusion phase, however, due to the exacerbation of oxidative stress, inflammatory responses, and mitochondrial damage, death receptors are activated, triggering both the extrinsic apoptotic pathway and the intrinsic apoptotic pathway, thereby accelerating the apoptotic process. | TNF-α, TNF-R, TRAIL, Fas, IRE1α, PERK, ATF4/6, Bcl-2, Bax, Bid, Bak, SIRT1 | FADD, caspase-3/8, Apaf-1, cytochrome c, dATP/ATP, caspase-9, CHOP, NF-κB, IL-34, miR-484, MOMP, JNK | |
Necroptosis | During the later reperfusion phase, necroptosis erupts. Massive amounts of inflammatory factors, like TNF-α, are generated, which activate RIPK1. When RIPK1 interacts with RIPK3 and MLKL, MLKL gets phosphorylated and then translocates to the cell membrane, thereby causing the cell membrane to be damaged. Meanwhile, the continuous opening of the mitochondrial MPTP releases CypD and other substances, which also facilitates the development of necroptosis. | TNF-α, PIPK1, PIPK3, MLKL, SIRT3, p53 | TAK1, MPTP, CypD, Drp1, CaMKII, NF-κB, ARC, Parkin, caspase-3/8 | |
Autophagy | During the ischemia period, autophagy gets activated as a result of the imbalance in intracellular energy metabolism and the build-up of metabolic waste. During the reperfusion stage, autophagy turns into a double-edged sword. While moderate autophagy remains protective, excessive autophagy can speed up cell death. | PI3K, AMPK, mTOR, HIF-1α, VDAC1, PERK, ATF6 | ULK1, ATG13, FIP200, p62, Beclin1, complex I, IRE1α, ATF4, PINK1, Parkin, Bcl-2, BNIP3, AKT, OPA1, CHOP | [81, 82, 85, 87, 89, 91, 93, 96, 97, 102, 108, 109, 113, 116] |
Pyroptosis | Pyroptosis initiates during the early stages of reperfusion, triggering acute I/R injury. It can be induced through two pathways: the caspase-1-dependent classical pathway and the caspase-4/5/11-dependent non-classical pathway. | LPS, NLRP3, Ca2+, ROS | IL-1β, IL-18, caspase-1, caspase-4/5/11,ASC, GSDMD, TLR4, MyD88, NF-κB, p65, p105, caspase-3, ZBP1, caspase-8 | [19, 119,120,121,122,123, 125,126,127, 134, 135, 142, 143, 151, 154] |
Ferroptosis | Ferroptosis is the predominant form of cell death in the late phase of myocardial I/R Injury. The mechanisms underlying ferroptosis involve complex interactions between iron accumulation, lipid peroxidation, and antioxidant system dysfunction. | Nrf2, Fe3+, PUFAs, NCOA4 | ACSL4, System Xc-, GSH, GPX4, SLC7A11, SLC3A2, FTH1, transferrin receptor, six transmembrane epithelial antigen of the prostate-3, MLKL | [132, 161, 163, 165, 167, 168, 170, 173, 174, 181, 188, 194] |
