Figure 6. Remifentanil preconditioning protects against hypoxia-induced cellular senescence and necroptosis in human cardiac myocytes that is achieved by remifentanil preconditioning-mediated decrease in the levels of cell cycle inhibitor p21, secretion of IL-8 proinflammatory cytokine as a part of senescence-associated secretory phenotype (SASP) and phospho-MLKL-based necroptotic signaling. Cellular senescence and necroptosis may be due to hypoxia-mediated oxidative stress (not shown). Moreover, necroptotic cells may release some proinflammatory signals (e.g., IL-8) that may also promote cellular senescence and then senescent cells may further stimulate the occurrence of other senescent cells by IL-8 signaling (black arrows). All these adverse effects can be reversed by remifentanil preconditioning.