Abstract
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.
Highlights
Exposure to brief periods of ischaemia and reperfusion has been recognized as a nonpharmacological approach to condition the heart to withstand a lethal dose of this stressor
Myriad complex mechanisms involving the activation of certain triggers promoting intracellular signalling such as the NO cascade, the reperfusion injury salvage kinase (RISK) pathway and the survival activating factor enhancement (SAFE) have been suggested to underlie the phenotypes of the conditioned heart.[3]
We have shown that in spite of lowering infarct size, PC affects neither the total expression of main necroptotic proteins (RIP1, RIP3, MLKL) nor post-translational modification of RIP3, an upstream activator of cytotoxic MLKL
Summary
Exposure to brief periods of ischaemia and reperfusion has been recognized as a nonpharmacological approach to condition the heart to withstand a lethal dose of this stressor. Myriad complex mechanisms involving the activation of certain triggers (metabolic products, autacoids, cytokines, neurotransmitters) promoting intracellular signalling such as the NO cascade, the reperfusion injury salvage kinase (RISK) pathway and the survival activating factor enhancement (SAFE) have been suggested to underlie the phenotypes of the conditioned heart.[3]. They can promote survival pathways and thereby mediate PC-induced cardiac salvage, the role of particular types of cell death is less understood and the importance of individual mechanisms is still a subject of investigation. Because increased reactive oxygen species (ROS) production has been associated with necroptosis induction and execution[17,21,22] and is consistently associated with detrimental postischaemic phenotypes[23] we investigated a possible mechanistic role of oxidative stress
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