Cardioprotection of ischaemic preconditioning is associated with inhibition of translocation of MLKL within the plasma membrane.

Necroptosis, a form of cell loss involving the RIP1-RIP3-MLKL axis, has been identified in cardiac pathologies while its inhibition is cardioprotective. We investigated whether the improvement of heart function because of ischaemic preconditioning is associated with mitigation of necroptotic signaling, and these effects were compared with a pharmacological antinecroptotic approach targeting RIP1. Langendorff-perfused rat hearts were subjected to ischaemic preconditioning with or without a RIP1 inhibitor (Nec-1s). Necroptotic signaling and the assessment of oxidative damage and a putative involvement of CaMKII in this process were analysed in whole tissue and subcellular fractions. Ischaemic preconditioning, Nec-1s and their combination improved postischaemic heart function recovery and reduced infarct size to a similar degree what was in line with the prevention of MLKL oligomerization and translocation to the membrane. On the other hand, membrane peroxidation and apoptosis were unchanged by either approach. Ischaemic preconditioning failed to ameliorate ischaemia-reperfusion-induced increase in RIP1 and RIP3 while pSer229-RIP3 levels were reduced only by Nec-1s. In spite of the additive phosphorylation of CaMKII and PLN because of ditherapy, the postischaemic contractile force and relaxation was comparably improved in all the intervention groups while antiarrhythmic effects were observed in the ischaemic preconditioning group only. Necroptosis inhibition seems to be involved in cardioprotection of ischaemic preconditioning and is comparable but not intensified by an anti-RIP1 agent. Changes in oxidative stress nor CaMKII signaling are unlikely to explain the beneficial effects.

Szobi A ，Farkašová-Ledvényiová V ，Lichý M ，Muráriková M ，Čarnická S ，Ravingerová T ，Adameová A ... -  《-》

CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis.

Zhang T ，Zhang Y ，Cui M ，Jin L ，Wang Y ，Lv F ，Liu Y ，Zheng W ，Shang H ，Zhang J ，Zhang M ，Wu H ，Guo J ，Zhang X ，Hu X ，Cao CM ，Xiao RP ... -  《-》

Necrostatin-1 Protects Against Paraquat-Induced Cardiac Contractile Dysfunction via RIP1-RIP3-MLKL-Dependent Necroptosis Pathway.

Zhang L ，Feng Q ，Wang T 《-》

Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis.

Liu X ，Zhang D ，Dong X ，Zhu R ，Ye Y ，Li L ，Jiang Y ... -  《-》

RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage.

Zhou H ，Liu L ，Ma X ，Wang J ，Yang J ，Zhou X ，Yang Y ，Liu H ... -  《-》