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Fig. 2 | Journal of Biomedical Science

Fig. 2

From: Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Fig. 2

Regulatory mechanism of necroptosis. Under ischemic conditions, TNF-α activated TNFR1 then triggered the assembly of complex I. The activation of caspase-8 would result in cardiomyocyte loss through apoptosis pathway while, the inactivation of caspase-8 in complex Iib induced the phosphorylation of RIPK1 and RIPK3 and formed pro-necrotic complexes or necrosomes. Then, the activated p-RIPK3 would phosphorylate MLKL to p-MLKL which will be translocated from cytoplasm to the plasma membrane and mediate membrane breakdown, leading to necroptotic cell death. Under prolongation of ischemic insult, the impairment of the autophagic machinery leads to accumulation of p62 which causes necroptosis dependent cell death. In addition, the intervention with several cell death modulators could improve cardiomyocyte viability under ischemic conditions. Pan-Caspase inhibitor Z-VAD acts as an effective caspase inhibitor resulting in prevention of apoptosis. Necroptosis is inhibited by Nec-1 which inhibits the activity of RIPK1 while Alliin prevents necroptosis cell death by mitigating necroptosis markers. TNF-α: tumor necrosis factor-α; TNFR1: tumor necrosis factor receptor 1; RIPK1: receptor-interacting serine/threonine-protein kinase 1; RIPK3: receptor-interacting serine/threonine-protein kinase 3; MLKL: mixed lineage kinase domain-like; p-MLKL: phosphorylated-mixed lineage kinase domain-like; Traf2: tumor necrosis factor receptor associated factor 2; cIAP1/2: cellular inhibitors of apoptosis 1 and 2; LUBAC: linear ubiquitin chain assembly complex; CYLD: the tumor-suppressor cylindromatosis; TRADD: TNFR1-associated death domain protein; FADD: fas-associated protein with death domain; Nec-1: necrostatin 1; zVAD: pan-Caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; LC3-II: lipid modified form of microtubule-associated protein 1A/1B-light chain 3; p62: ubiquitin-binding protein p62

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