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Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1-RIP3-MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-[alpha], which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-[alpha]-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia. Key words: myocardial ischemia, ischemic preconditioning, heart failure, cell death, necroptosis, passive necrosis. Resume: L'ischemie de longue duree peut mener a une perte de cellules, mais des episodes repetes d'ischemie breve entrainent une augmentation de la resistance du creur aux effets deleteres d'episodes subsequents d'ischemie prolongee et favoriser la survie des cellules. Classiquement, on croit que l'apport de sang au creur ischemique est associe a la liberation de cytokines, a l'activation de la reaction inflammatoire et a la mort cellulaire par un processus necrotique. Au cours des dernieres annees, ce paradigme de necrose passive en tant que mort cellulaire incontrolee a ete revu, et on a documente l'existence d'une forme de mort cellulaire par un processus necrotique regule de maniere stricte : la necroptose. Cette modalite controlee de mort cellulaire, rassemblant toutes les caracteristiques morphologiques de la necrose, a ete etudiee dans differents types de lesions cardiaques associees a l'ischemie. On a decouvert que le processus de necroptose depend de l'activation de l'axe RIP1-RIP3-MLKL, ce qui favorise des changements menant a la rupture de la membrane cellulaire. Cette voie de signalisation est activee par le TNF-[alpha], que l'on a aussi lie a la voie de signalisation de cardioprotection du preconditionnement ischemique. Par consequent, cet article de synthese tend a decrire la signalisation dont la mediation est assuree par le TNF-[alpha] et qui peut mener a la survie des cellules ou a la mort cellulaire necroptotique. De plus, nous discutons de certaines donnees experimentales laissant entrevoir qu'il existe un lien entre le dysfonctionnement du creur et la perte de cellules causee par la necroptose dans diverses affections liees a l'ischemie myocardique. [Traduit par la Redaction] Mots-cles: ischemie myocardique, preconditionnement ischemique, insuffisance cardiaque, mort des cellules, necroptose, necrose passive., Introduction In spite of the increased knowledge for the promotion of positive effects of a healthy lifestyle as well as effective therapeutical approaches, the mortality of patients with ischemia-associated heart [...]

Although [Ca.sup.2+]/calmodulin-dependent protein kinase II delta (CaMKUU) has been implicated in development of different phenotypes of myocardial ischaemia-reperfusion injury, its involvement in arrhythmogenesis and cardiac stunning is not sufficiently elucidated. Moreover, the mechanisms by which CaMKII[delta] mediates disturbances in excitation-contraction coupling, are not exactly known. To investigate this, KN-93 (0.5 [micro]mol/L), a CaMKII inhibitor, was administered before induction of global ischaemia and reperfusion in isolated Langendorff-perfused rat hearts. Expression of CaMKII[delta] and the sarcollemal [Ca.sup.2+]-cycling proteins, known to be activated during reperfusion, was analyzed using immunoblotting. KN-93 reduced reperfusion-induced ectopic activity and the incidence of ventricular fibrillation. Likewise, the severity of arrhythmias was lower in KN-treated hearts. During the pre-ischaemia phase, neither inotropic nor chronotropic effects were elicited by KN-93, whereas post-ischaemic contractile recovery was significantly improved. Ischaemia--reperfusion increased the expression of CaMKII[delta] and sodium-calcium exchanger (NCX1) proteins without any influence on the protein content of alpha 1c, a pore-forming subunit of L-type calcium channels (LTCCs). On the other hand, inhibition of CaMKII normalized changes in the expression of CaMKII[delta] and NCX1. Taken together, CaMKII[delta] seems to regulate its own turnover and to be an important component of cascade integrating NCX1, rather than LTCCs that promote ischaemia--reperfusion-induced contractile dysfunction and arrhythmias. Key words: [Ca.sup.2+]calmodulin-dependent protein kinase II, myocardial ischaemia-reperfusion, L-type calcium channel, sodium-calcium exchanger, arrhythmias. Meme si la proteine kinase dependante du [Ca.sup.2+] et de la calmoduline II delta (CaMKII[delta]) a ete impliquee dans le developpement de differents phenotypes de lesions resultant de l'ischemie-reperfusion du myocarde, son implication dans l'arythmogenese et la sideration cardiaque n'est pas suffisamment elucidee. De plus, les mecanismes par lesquels la CaMKUU agit sur les dereglements du couplage excitation-contraction ne sont pas exactement connus. Afin d'etudier ceci, du KN-93, un inhibiteur de CaMKII, a ete administre prealablement a l'induction d'une ischemie globale et d'une reperfusion sur des coeurs de rats isoles, perfuses selon la methode de Langendorff. L'expression de la CaMKII[delta] et des proteines du cycle du [Ca.sup.2+] du sarcolemme, connues pour etre activees lors de la reperfusion, a ete analysee par immunobuvardage. Le KN-93 reduisait l'activite ectopique induite par la reperfusion et l'incidence de la fibrillation ventriculaire. De plus, l'arythmie etait moins severe dans les coeurs traites au KN. Lors de la phase pre-ischemique, le KN-93 n'induisait pas d'effets inotropes ou chronotropes alors que la recuperation de l'activite contractile post-ischemique etait significativement amelioree. L'ischemie-reperfusion augmentait l'expression de la CaMKUU et de l' echangeur sodium-calcium (NCX1) sans influencer le contenu en alpha 1c, une sous-unite qui forme le pore des canaux calciques de type L (LTCC). En revanche, l'inhibition de la CaMKII normalisait les modifications de l'expression de la CaMKII[delta] et du NCX1. En conclusion, la CaMKII[delta] semble reguler son propre turnover et etre une composante importante de la cascade integrant NCX1 plutot que LTCC qui favorise la dysfonction contractile et l'arythmie induites par l'ischemie--reperfusion. Mots-cles : proteine kinase dependante du [Ca.sup.2+] et de la calmoduline II, ischemie-reperfusion du myocarde, canaux calciques de type L, echangeur sodium-calcium, arythmie. [Traduit par la Redaction], Introduction Although restoration of coronary flow in previously ischaemic myocardium is the only prerequisite of heart salvage, reperfusion itself may have deleterious effects leading to disturbances in heart rhythm, contractile [...]

Background: It is known that statins possess beneficial cardioprotective effects irrespective of lipidlowering action and that cardiac injury due ischemia/reperfusion is associated with Ca2+ dysregulation resulting in contractile dysfunction., Objective: With this background, we tested a hypothesis that simvastatin influences signaling of Ca2+/calmodulindependent protein kinase IIδ (CaMKIIδ), a protein kinase regulating both Ca2+ homeostasis and thick filament function, and thereby might underlie the mitigation of ischemia/reperfusion (I/R)-induced cardiac dysfunction., Method: Isolated hearts of control and simvastatin-treated (p.o. 10 mg/kg, 5 days) rats were subjected to global I and R and Western blotting was used to study the expression/activation of certain signaling proteins., Results: Simvastatin treatment did not modify the plasma lipid levels; however, it recovered depressed cardiac performance and reduced reperfusion arrhythmias without affecting the activation of CaMKIIδ through phosphorylation of Thr287. Activation of its downstreams, such as phospholamban (PLN) and cardiac myosin-binding protein C (cMyBP-C) at Thr17 and Ser282, respectively, was in accordance with the levels of pThr287-CaMKIIδ. Total expression of these proteins, however, did not follow the same pattern and was either unchanged (CaMKIIδ, cMYBP-C) or increased (PLN). Likewise, PLN/SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a) ratio in I/R hearts was unaffected by the treatment. On the other hand, simvastatin reversed the increased protein expression of protein phosphatase 1β (PP1β), but not protein phosphatase 2A (PP2A), in I/R hearts., Conclusion: A lower rate of dephosphorylation and thereby a delay in inactivation of phosphorylated proteins due to a decrease in PP1β, rather than effects on phosphorylation of CaMKIIδ and its downstreams, such as PLN and cMyBP-C, may underlie beneficial effects of simvastatin in I/R hearts., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)