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Aim: The transcriptional factor HIF‐1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF‐1α and increase myocardial ischemic tolerance. However, the precise role of HIF‐1α in mediating the protective effect remains incompletely understood. Methods: Male wild‐type (WT) mice and mice with partial Hif1a deficiency (hif1a+/−) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA‐sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy. Results: We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a+/− mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3‐II/LC3‐I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi‐1) abolished the infarct size‐limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH‐induced cardioprotection. Conclusion: These findings provide new insights into the contribution of HIF‐1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway. [ABSTRACT FROM AUTHOR]

Currently, there are no satisfactory interventions to protect the heart against the detrimental effects of ischemiareperfusion injury. Although ischemic preconditioning (PC) is the most powerful form of intrinsic cardioprotection, its application in humans is limited to planned interventions, due to its short duration and technical requirements. However, many organs/tissues are capable of producing 'remote' PC (RPC) when subjected to brief bouts of ischemia- reperfusion. RPC was first described in the heart where brief ischemia in one territory led to protection in other area. Later on, RPC started to be used in patients with acute myocardial infarction, albeit with ambiguous results. It is hypothesized that the connection between the signal triggered in remote organ and protection induced in the heart can be mediated by humoral and neural pathways, as well as via systemic response to short sublethal ischemia. However, although RPC has a potentially important clinical role, our understanding of the mechanistic pathways linking the local stimulus to the remote organ remains incomplete. Nevertheless, RPC appears as a cost-effective and easily performed intervention. Elucidation of protective mechanisms activated in the remote organ may have therapeutic and diagnostic implications in the management of myocardial ischemia and lead to development of pharmacological RPC mimetics. Key words: ischemia-reperfusion, myocardial infarction, remote preconditioning, innate cardioprotection, cell signaling. Resume: Il n'existe actuellement aucune intervention permettant de proteger le coeur de maniere satisfaisante contre les effets deleteres des lesions d'ischemie-reperfusion. Meme si le preconditionnement ischemique (PC) constitue la plus puissante forme de cardioprotection intrinseque, son application chez l'homme se limite a des interventions planifiees, en raison de sa courte duree et des techniques necessaries. Cependant, bien des organes et des tissus sont en mesure de produire un PC << a distance >> (PCD) quand ils sont soumis a de brefs episodes d'ischemie-reperfusion. Le PCD a tout d'abord ete decrit pour des coeurs dans lesquels une breve ischemie d'un territoire donne menait a une protection dans une autre region. Par la suite, on a commence a autiliser le PCD chez des patients atteints d'infarctus du myocarde aigu, mais les resultats sont demeures ambigus. On a formule une hypothese selon laquelle la connexion entre le signal declenche dans un organe distant et la protection obtenue dans le coeur pourrait etre mediee par des voies de signalisation humorales et nerveuses, ainsi que par l'intermediaire d'une reaction generale a une ischemie subletale de courte duree. Cependant, bien que le PCD puisse eventuellement jouer un role important en clinique, notre comprehension des voies mecaniques liant le stimulus local a l'organe distant demeure incomplete. Neanmoins, le PCD semble correspondre a une intervention rentable et facile a effectuer. L'elucidation des modes d'action protecteurs qui sont actives dans l'organe distant pourrait avoir des retombees sur la prise en charge de l'ischemie myocardique en fournissant des outils therapeutiques et diagnostiques. Cela pourrait mener au developpement d'agents pharmacologiques mimant le PCD. [Traduit par la Redaction] Mots-cles: ischemie-reperfusion, infarctus du myocarde, pre conditionnement a distance, cardioprotection innee, signalization cellulaire., Introduction Ischemic heart disease--in particular, its most serious manifestation, an acute myocardial infarction (AMI)--still remains the number-one cause of death in the modern world. Early restoration of blood flow in [...]

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 [...]

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia-reperfusion injury. Phospholipases [A.sub.2] (PL[A.sub.2]s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PL[A.sub.2] ([cPLA.sub.2][alpha]), its phosphorylated form (p-[cPLA.sub.2][alpha]), calcium-independent ([iPLA.sub.2]), and secretory ([sPLA.sub.2]IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PL[A.sub.2]s expression and phospholipid FA remodeling. While CIH did not affect PL[A.sub.2]s mRNA levels, it increased the total [cPLA.sub.2][alpha] protein in cytosol and membranes (by 191% and 38%, respectively) and p-[cPLA.sub.2][alpha] (by 23%) in membranes. On the contrary, both [iPLA.sub.2] and [sPLA.sub.2]IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced [cPLA.sub.2][alpha] up-regulation and its phosphorylation on [Ser.sup.505]. Our results show that CIH diversely affect myocardial PL[A.sub.2]s and suggest that ROS are responsible for the activation of [cPLA.sub.2][alpha] under these conditions. Key words: heart, chronic intermittent hypoxia, oxidative stress, phospholipases [A.sub.2], tempol. L'adaptation a l'hypoxie intermittente chronique (HIC) est associee a la production de derives reactifs de l'oxygene (ou ROS pour <>) jouant un role dans l'amelioration de la tolerance du creur aux lesions aigues d'ischemiereperfusion. Les phospholipases [A.sub.2] (PL[A.sub.2]) jouent un role important dans le metabolisme des phospholipides, qui influencent l'homeostasie de la membrane des cardiomyocytes. Dans ces travaux, nous visions a etablir l'effet de l'HIC (7000 m, 8 h/jour, 5 semaines) sur l'expression de la PL[A.sub.2] cytosolique ([cPLA.sub.2][alpha]), de sa forme phosphorylee (p-[cPLA.sub.2][alpha]), independante du calcium ([iPLA.sub.2]) et secretaire ([sPLA.sub.2]IIA) pour les taux proteiques et d'ARNm, ainsi que sur le profil des acides gras (AG) dans le ventricule gauche de rats Wistar males adultes. Nous avons utilise l'administration chronique de tempol, un antioxydant, afin de verifier le role des ROS sur l'effet de l'HIC dans l'expression des PL[A.sub.2] et le remodelage des AG phospholipidiques. Alors que l'HIC n'affectait pas les taux d'ARNm des PL[A.sub.2], elle entramait une augmentation des taux de proteines [cPLA.sub.2][alpha] dans le cytosol et les membranes (de 191 et de 38%, respectivement) et de p-[cPLA.sub.2][alpha] (de 23%) dans les membranes. Par contre, l'[iPLA.sub.2] et la [sPLA.sub.2]IIA etaient toutes deux regulees a la baisse avec l'HIC. L'HIC a aussi entrame une diminution des taux d'AG phospholipidiques n-6 polyinsatures (ou PUFA pour<>) ainsi que la proportion de PUFA n-3. L'administration de tempol a permis de prevenir uniquement la regulation a la hausse de la [cPLA.sub.2][alpha] que provoquait l'HIC, ainsi que sa phosphorylation sur la [Ser.sup.505]. Nos resultats montrent que l'HIC affecte de facon diverse les PL[A.sub.2] myocardiques et laisse entendre que les ROS seraient responsables de l'activation de la [cPLA.sub.2][alpha] dans ces conditions. [Traduit par la Redaction] Mots-cles: creur, hypoxie intermittente chronique, stress oxydatif, phospholipases [A.sub.2], tempol., Introduction Exposure to chronic intermittent hypoxia (CIH) leads to adaptive structural and functional changes of the heart that help in maintaining homeostasis with minimum energy expenditure (Ostadal and Kolar 2007). [...]

Although pleiotropy, which is defined as multiple effects derived from a single gene, was recognized many years ago, and considerable progress has since been achieved in this field, it is not very clear how much this feature of a drug is clinically relevant. During the last decade, beneficial pleiotropic effects from hypolipidemic drugs (as in, effects that are different from the primary ones) have been associated with reduction of cardiovascular risk. As with statins, the agonists of peroxisome proliferator-activated receptors (PPARs), niacin and fibrates, have been suggested to exhibit pleiotropic activity that could significantly modify the outcome of a cardiovascular ailment. This review examines findings demonstrating the impacts of treatment with hypolipidemic drugs on cardiac response to ischemia in a setting of acute ischemia-reperfusion, in relation to PPAR activation. Specifically, it addresses the issue of susceptibility to ischemia, with particular regard to the preconditioning-like cardioprotection conferred by hypolipidemic drugs, as well as the potential molecular mechanisms behind this cardioprotection. Finally, the involvement of PPAR activation in the mechanisms of non-metabolic cardioprotective effects from hypolipidemic drugs, and their effects on normal and pathologically altered myocardium (in the hearts of hypertensive rats) is also discussed. Key words: acute myocardial ischemia-reperfusion, hypolipidemic drugs, pleiotropic effects, PPARα activation. Bien que l'action pleiotropique caracterisee par la manifestation d'effets multiples derivant d'un gene unique ait ete reconnue il y a bien des annees et que des progres considerables aient ete realises dans ce domaine, la portee clinique de cette caracteristique des medicaments n'est pas tres bien definie. Au cours de la derniere decennie, on a montre que les bienfaits tires des effets pleiotropiques des medicaments hypolipidemiants (differents de leurs effets principaux) sous-tendent la reduction du risque cardiovasculaire. De maniere similaire aux statines, on a laisse entendre que la niacine et les fibrates, des agonistes des recepteurs actives par les proliferateurs des peroxisomes (PPARs), ont une action pleiotropique, ce qui pourrait moduler de maniere appreciable l'issue des maladies cardiovasculaires. Le present article fait la synthese certaines observations mettant en evidence les effets du traitement par des medicaments hypolipidemiants sur la reponse du creur a l'ischemie dans un contexte d'ischemie-reperfusion, et ce, en correlation avec l'activation des PPAR. Tout particulierement, cet article traite du probleme de la susceptibilite a l'ischemie en lien direct avec la cardioprotection de type preconditionnement que procurent les medicaments hypolipidemiants, ainsi qu'avec ses eventuels mecanismes moleculaires sous-jacents. Enfin, nous discutons aussi du role de l'activation des PPAR parmi les mecanismes des effets cardioprotecteurs non metaboliques des medicaments hypolipidemiants ainsi que de son role dans le myocarde normal ou pathologique (dans les creurs de rats hypertendus). [Traduit par la Redaction] Mots-cles: ischemie aigue-reperfusion du myocarde, medicaments hypolipidemiants, effets pleiotropiques, activation des PPARα., Introduction Pleiotropy as an important pharmacodynamic feature of drugs Most drugs used in the treatment of cardiovascular diseases are assumed to have more than one pharmacodynamic action. Therefore, the end-points [...]

Cardiac sensitivity to oxygen deprivation changes significantly during ontogenetic development. However, the mechanisms for the higher tolerance of the immature heart, possibilities of protection, and the potential impact of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults have not yet been satisfactorily clarified. The hypoxic tolerance of an isolated rat heart showed a triphasic pattern: significant decrease from postnatal day 1 to 7, followed by increase to the weaning period, and final decline to adulthood. We have observed significant ontogenetic changes in mitochondrial oxidative phosphorylation and mitochondrial membrane potential, as well as in the role of the mitochondrial permeability transition pores in myocardial injury. These results support the hypothesis that cardiac mitochondria are deeply involved in the regulation of cardiac tolerance to oxygen deprivation during ontogenetic development. Ischemic preconditioning failed to increase tolerance to oxygen deprivation in the highly tolerant hearts of newborn rats. Chronic hypoxic exposure during early development may cause in-utero or neonatal programming of several genes that can change the susceptibility of the adult heart to ischemia-reperfusion injury; this effect is sex dependent. These results would have important clinical implications, since cardiac sensitivity in adult patients may be significantly affected by perinatal hypoxia in a sex-dependent manner. Key words: immature heart, ontogeny, hypoxic tolerance, cardiac protection. La sensibilite cardiaque a la privation d'oxygene change significativement au cours de l'ontogenie. Cependant, les mecanismes responsables de la tolerance plus elevee du coeur immature, ainsi que les possibilites de protection et de l'impact potentiel d'une hypoxie perinatale sur la tolerance cardiaque a la privation d'oxygene chez les adultes n'ont pas encore ete clarifies de maniere satisfaisante. La tolerance hypoxique du coeur de rat isole a revele un patron triphasique : une diminution significative du jour post-natal 1 au jour 7, suivie d'une augmentation lors du sevrage et d'un declin final a l'age adulte. Les auteurs ont observe des changements ontogeniques significatifs sur le plan de la phosphorylation oxydative mitochondriale, du potentiel membranaire mitochondrial, ainsi que du role des pores de transition de permeabilite de la mitochondrie dans le dommage myocardique. Ces resultats appuient l'hypothese que les mitochondries cardiaques sont profondement impliquees dans la regulation de la tolerance cardiaque a la privation d'oxygene durant l'ontogenie. Le pre-conditionnement ischemique ne parvenait pas a augmenter la tolerance a la privation d'oxygene chez les coeurs de rats nouveau-nes, hautement tolerants. L'exposition chronique a l'hypoxie, tot dans le developpement, peut induire la programmation in utero ou neonatale de plusieurs genes qui peuvent modifier la susceptibilite du coeur adulte au dommage d'ischemie/reperfusion; cet effet est dependant du sexe. Ces resultats pourraient avoir des implications cliniques importantes, puisque la sensibilite des patients adultes peut etre significativement affectee par l'hypoxie perinatale de maniere dependante du sexe. [Traduit par la Redaction] Mots-cles : coeur immature, ontogenie, tolerance hypoxique, protection cardiaque., Introduction The most frequent (and hence the most widely studied) cardiovascular diseases of modern times undoubtedly include hypoxic states. They originate as a result of disproportion between the amount of [...]

N6-methyladenosine (m6A) is an abundant mRNA modification affecting mRNA stability and protein expression. It is a highly dynamic process, and its outcomes during postnatal heart development are poorly understood. Here we studied m6A machinery in the left ventricular myocardium of Fisher344 male and female rats (postnatal days one to ninety; P1-P90) using Western Blot. A downward pattern of target protein levels (demethylases FTO and ALKBH5, methyltransferase METTL3, reader YTHDF2) was revealed in male and female rats during postnatal development. On P1, the FTO protein level was significantly higher in males compared to females. [ABSTRACT FROM AUTHOR]