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How oxygen is sensed by the heart and what mechanisms mediate its sensing remain poorly understood. As recent reports show that low P[O.sub.2] levels are detected by the cardiomyocytes in a few seconds, the rapid and short applications of low levels of oxygen (acute hypoxia), which avoid multiple effects of chronic hypoxia, may be used to probe the oxygen-sensing pathway of the heart. Here, we explored the oxygen-sensing pathway, focusing primarily on cellular surface membrane proteins that were first exposed to low P[O.sub.2]. Such studies suggest that acute hypoxia primarily targets the cardiac calcium channels, where either the channel itself or moieties closely associated with it, for instance heme-oxygenase-2 (HO-2) interacting through kinase phosphorylation, signal the [alpha]-subunit of the channel to the altered levels of P[O.sub.2]. Amino acids 1572-1651, the CaMKII phosphorylation sites (S1487 and S1545), CaM-binding sites (I1624 and Q1625), and Ser1928 of the carboxyl tail of the [alpha]-subunit appear to be critical residues that sense oxygen. Future studies on HO-2 knockout mice or CRISPR/Cas9 gene-edited human-induced pluripotent stem-cell-derived cardiomyocytes that reduce CaM-binding affinity are likely to provide deeper insights into the [O.sub.2]-sensing mechanisms. Key words: acute hypoxia, calcium channel, oxygen sensor, cardiomyocytes, CaMKII, heme-oxygenase-2 On ne comprend pas encore tres bien comment le coeur detecte l'oxygene ni les modes d'action qui y sont lies. Comme de recentes publications montrent que les cardiomyocytes peuvent detecter des diminutions de la P[O.sub.2] en quelques secondes, il est possible que l'administration d'oxygene a de faibles concentrations rapidement et sur de courtes durees (hypoxie aigue), ce qui permet d'eluder lesmultiples effets de l'hypoxie chronique, puisse permettre de sonder les voies de signalisation de la detection de l'oxygene dans le coeur. Dans les presents travaux, nous explorons les voies de signalisation de la detection de l'oxygene, en nous centrant principalement sur les proteines de surface desmembranes cellulaires, premier endroit expose a un abaissement de la P[O.sub.2]. De telles etudes laissent entendre que l'hypoxie aigue ciblerait principalement les canaux calciques cardiaques, soit les canaux eux-memes ou certains fragments qui leur sont etroitement associes. Par exemple, l'heme-oxygenase 2 (HO-2) interagit avec la sous-unite [alpha] des canaux par l'intermediaire de la phosphorylation kinasique pour signaler la modification des taux de P[O.sub.2]. Les acides amines 1572-1651, les sites de phosphorylation de la CaMKII (S1487 et S1545), le site de liaison de la CaM (I1624, Q1625) et la Ser1928 de l'extremite carboxyl de la sous-unite [alpha] semblent constituer des residus cruciaux pour la detection de l'oxygene. De futures etudes a l'aide de souris << knockout >> pour l'HO-2 ou avec les hiPSC-CM dont CRISPR/Cas9 sont modifies ou l'affinite de liaison de la CaM est abaissee sont susceptibles de fournir plus de renseignements quant aux modes d'action de la detection de l'[O.sub.2]. [Traduit par la Redaction] Mots-cles : hypoxie aigue, canal calcique, detecteur d'oxygene, cardiomyocytes, CaMKII, heme-oxygenase-2, 1. Introduction Ischemic heart disease is a leading cause of death worldwide, with its global prevalence expected to exceed 1900 cases per 100000 populations by 2030 (Nowbar et al. 2019). [...]

Diabetes dramatically increases the risk of cardiovascular complications. The endothelial dysfunction and diastolic heart dysfunction are associated with a decreasing level of hydrogen sulfide ([H.sub.2]S) and inhibition of the activity of endothelial nitric oxide synthase (NOS) in diabetes. The aim of this study is to investigate the effect of modulation of [H.sub.2]S synthesis on heart functions and vasorelaxation in diabetes. The DL- propargylglycine and L-cysteine were administered intraperitoneally. [H.sub.2]S content in the heart tissue, markers of oxidative stress, inducible NOS and constitutive NOS (cNOS) activities, endothelium-dependent vasorelaxation of the aortic rings, and heart function were studied. We demonstrate that our combination increased [H.sub.2]S synthesis 13 times and cNOS activity 5 times in the heart tissue of diabetic rats. Increasing NO and [H.sub.2]S production caused improvement and restoration of endothelium- dependent relaxation of aorta, effective arterial elastance, and diastolic heart function in diabetic rats. The endothelium- dependent relaxation increased 2.4 times; effective arterial elastance decreased by 47%. The end-diastolic myocardial stiffness decreased 2.2 times. Thus, modulation of [H.sub.2]S synthesis leads to increased cNOS activity by up to 5 times in the cardiovascular system. Increasing NO and [H.sub.2]S production restored endothelium-dependent relaxation of aorta and improved heart function in diabetes. Key words: hydrogen sulfide, diabetes, cNOS and iNOS activity, oxidative stress, DL-propargylglycine, L-cysteine, heart functions, endothelium-dependent relaxation. Le diabete entraine un accroissement spectaculaire du risque de complications cardiovasculaires. Les dysfonctionnements endothelial et diastolique du creur sont associes a un abaissement des taux de sulfure d'hydrogene ([H.sub.2]S) ainsi qu'a une inhibition de l'activite de la NO-synthase endotheliale dans le diabete. Ces travaux avaient pour but d'etudier l'effet de la modulation de la synthese du [H.sub.2]S sur le fonctionnement du creur et la vasorelaxation dans le diabete. Nous avons administre de la DL-propargylglycine et de la L-cysteine par voie intraperitoneale. Nous avons etudie les taux de [H.sub.2]S dans le tissu cardiaque, des marqueurs du stress oxydatif, l'activite de l'iNOS et de la cNOS, la vasorelaxation d'anneaux aortiques dependante de l'endothelium ainsi que le fonctionnement du creur. Nous montrons que notre association de composes entrainait une stimulation de la synthese de [H.sub.2]S par un facteur de 13 et de l'activite de la cNOS par un facteur de 5 dans le tissu cardiaque de rats atteints de diabete. Chez les rats atteints de diabete, l'augmentation de la production de NO et de [H.sub.2]S a permis l'amelioration et le retablissement de la relaxation de l'aorte dependante de l'endothelium, de l'elastance arterielle effective et de la fonction diastolique du creur. Nous avons observe une augmentation de la relaxation dependante de l'endothelium par un facteur de 2,4 avec une diminution de l'elastance arterielle effective de l'ordre de 47 %. Nous avons observe une diminution de la rigidite telediastolique par un facteur de 2,2. Par consequent, la modulation de la synthese du [H.sub.2]S mene a une augmentation de l'activite de la cNOS par un facteur de 5 dans le systeme cardiovasculaire. L'augmentation de la production de NO et de [H.sub.2]S permettait le retablissement de la relaxation de l'aorte dependante de l'endothelium et l'amelioration du fonctionnement du creur dans le diabete. [Traduit par la Redaction] Mots-cles : sulfure d'hydrogene, diabete, activite de la cNOS et de l'iNOS, stress oxydatif, DL-propargylglycine, L-cysteine, fonctionnement du creur, relaxation dependante de l'endothelium., 1. Introduction Worldwide, over 463 million people have diabetes. The number of patients with diabetes is projected to reach 700 million by 2045 (IDF Atlas 9th Edition and Other Resources [...]

With the surgical improvement of congenital heart disease, Fontan operation has been applied to many complicated patients in recent years. This is the first report of a child with panhypopituitarism who underwent Fontan operation. A 5-year-old boy was scheduled for Fontan operation. He previously underwent Blalock-Taussig shunt and bidirectional Glenn operations for univentricular heart with double-outlet right ventricle and pulmonary atresia. He was receiving hydrocortisone and 1-desamino-8-D-arginine vasopressin (DDAVP) for panhypopituitarism secondary to removal of craniopharyngioma performed at the age of three years. Although urine output and serum sodium concentration were adequately controlled by adjustment of vasopressin infusion rate during surgery, massive pleural effusions and ascites developed postoperatively, which required several days for control by adjusting the dose of oral DDAVP and normalize the serum sodium level. Intraoperative management of Fontan operation for a patient with panhypopituitarism was controllable by appropriate hormone replacement. However, postoperative fluid management was complicated by the clinical features of panhypopituitarism and Fontan physiology., Author(s): Kohei Sunoki [sup.1], Yoji Otsuka [sup.1], Hidetaka Iwai [sup.1], Tatsuya Nagano [sup.1], Naoyuki Taga [sup.1], Masaaki Kawada [sup.2], Mamoru Takeuchi [sup.1] [sup.3] Author Affiliations: (1) grid.410804.9, 0000000123090000, Department of [...]

Recent studies have suggested that lymphatics help to restore heart function after cardiac injury.sup.1-6. Here we report that lymphatics promote cardiac growth, repair and cardioprotection in mice. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls the proliferation and survival of cardiomyocytes during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction. Embryos that lack LECs develop smaller hearts as a consequence of reduced cardiomyocyte proliferation and increased cardiomyocyte apoptosis. Culturing primary mouse cardiomyocytes in LEC-conditioned medium increases cardiomyocyte proliferation and survival, which indicates that LECs produce lymphoangiocrine signals that control cardiomyocyte homeostasis. Characterization of the LEC secretome identified the extracellular protein reelin (RELN) as a key component of this process. Moreover, we report that LEC-specific Reln-null mouse embryos develop smaller hearts, that RELN is required for efficient heart repair and function after neonatal myocardial infarction, and that cardiac delivery of RELN using collagen patches improves heart function in adult mice after myocardial infarction by a cardioprotective effect. These results highlight a lymphoangiocrine role of LECs during cardiac development and injury response, and identify RELN as an important mediator of this function. Lymphatic endothelium secretes factors needed for heart growth and repair such as RELN, which helps with heart regeneration and cardioprotection after myocardial infarction., Author(s): Xiaolei Liu [sup.1] , Ester De la Cruz [sup.2] , Xiaowu Gu [sup.3] , Laszlo Balint [sup.4] [sup.5] , Michael Oxendine-Burns [sup.1] , Tamara Terrones [sup.6] , Wanshu Ma [...]

The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg*[kg.sup.-1]*[day.sup.-1], FA 5 mg*[kg.sup.-1]*[day.sup.-1]; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg*[kg.sup.-1]*[day.sup.-1], FA 5 mg*[kg.sup.-1]*[day.sup.-1]; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis. Key words: heart failure, monocrotaline, vitamin B6, folic acid, oxidative stress, rat. Cette etude avait pour but de confronter l'hypothese selon laquelle l'application subchronique de vitamine B6 et d'acide folique (AF) de maniere concomitante peut affecter l'insuffisance cardiaque (IC) provoquee par la monocrotaline (MCT), avec la modulation de parametres du stress oxydatif ainsi que de biomarqueurs cardiometaboliques. Nous avons procede a une etude biochimique et histomorphometrique chez des rats Wistar albinos males (masse corporelle de 160 g au depart) : temoins exposes a une solution a blanc (T1 solution saline physiologique a 1 mL/kg pendant un jour, n = 8; T2 solution saline physiologique a 1 mL/kg sur 28 jours, n = 8), IC provoquee par la MCT (MCT a 50 mg/kg, n = 8), B6+AF (vitamine B6 a 7 mg*[kg.sup.-1]*[jour.sup.-1], AF a 5 mg*[kg.sup.-1]*[jour.sup.-1]; n = 8) et MCT+B6+AF (MCT a 50 mg/kg, vitamine B6 a 7 mg*[kg.sup.-1]*[jour.sup.-1], AF a 5 mg*[kg.sup.-1]*[jour.sup.-1]; n = 8). Dans le tissu cardiaque, nous avons etabli l'activite de la superoxyde dismutase et de la glutathion peroxidase, avec la quantite de groupements thiol-, carbonyl et nitrotyrosine. Nous avons confirme l'IC provoquee par la MCT a l'aide de l'echocardiographie. En cas d'IC provoquee par la MCT, nous avons observe une hypertrophie de la paroi ventriculaire droite, accompagnee d'une hausse marquee de la troponine T, avec preservation du fonctionnement des reins et du foie. Cependant, ces effets n'etaient pas lies aux effets antioxydants de la vitamine B6 et de l'AF, puisque plusieurs parametres du stress oxydatif etaient accentues apres leur administration. Dans cette etude, l'administration concomitante de vitamine B6 et d'AF n'a pas permis d'attenuer l'hypertrophie de la paroi ventriculaire droite, mais entrainait une aggravation du stress oxydatif, lequel joue un role dans la pathogenese de l'IC. [Traduit par la Redaction] Mots-cles : insuffisance cardiaque, monocrotaline, vitamine B6, acide folique, stress oxydatif, rat., Introduction One of the experimental methods for inducing heart failure (via pulmonary arterial hypertension (PAH)) is achieved by the application of monocrotaline (MCT). PAH is characterized by remodeling mechanisms of [...]

The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, [Ca.sup.2+]-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy. Key words: cardiac hypertrophy, cardiac remodeling, pathological cardiac hypertrophy, physiological cardiac hypertrophy, adaptive cardiac hypertrophy, cardiac contractile function. Le coeur est capable de reagir a des situations de stress par une augmentation de sa masse musculaire, que l'on caracterise plus largement comme etant de l'hypertrophie cardiaque. Ce phenomene permet de reduire au minimum la tension de la paroi ventriculaire dans un coeur soumis a une charge de travail plus elevee que normalement. Aux premiers stades, l'hypertrophie cardiaque est associee avec une fonction cardiaque normale ou amelioree et est consideree comme etant adaptative ou physiologique; toutefois, a des stades plus tardifs, si le stimulus n'est pas ecarte, elle est associee avec un dysfonctionnement contractile et alors nommee hypertrophie cardiaque pathologique. C'est pendant l'hypertrophie cardiaque physiologique que le fonctionnement des organites sous-cellulaires, y compris le sarcolemme, le reticulum sarcoplasmique, les mitochondries et les myofibrilles peut etre regule a la hausse, tandis que l'hypertrophie cardiaque pathologique est associee avec une regulation a la baisse de ces activites sous-cellulaires. La transition de l'hypertrophie cardiaque physiologique vers l'hypertrophie cardiaque pathologique pourrait etre le fait d'une diminution de l'apport sanguin au myocarde hypertrophie comme consequence de la diminution de la densite des capillaires. On laisse entendre que le stress oxydatif, les processus inflammatoires, les anomalies de la gestion des ions [Ca.sup.2+] dans les cardiomyocytes ainsi que l'apoptose joueraient des roles critiques dans la depression de la fonction contractile au cours du developpement de l'hypertrophie pathologique. [Traduit par la Redaction] Mots-cles : hypertrophie cardiaque, remodelage cardiaque, hypertrophie cardiaque pathologique, hypertrophie cardiaque physiologique, hypertrophie cardiaque adaptative, fonction cardiaque contractile., Introduction The heart adapts to a sustained increase in blood pressure, or a sustained increase in blood volume, by increasing cardiac muscle mass and this growth in myocardium is broadly [...]

Stress responses are important to human physiology and pathology, and the inability to adapt to cellular stress leads to cell death. To mitigate cellular stress and re-establish homeostasis, cells, including those in the cardiovascular system, activate stress coping response mechanisms. The endoplasmic reticulum, a component of the cellular reticular network in cardiac cells, mobilizes so-called endoplasmic reticulum stress coping responses, such as the unfolded protein response. MicroRNAs play an important part in the maintenance of cellular and tissue homeostasis, perform a central role in the biology of the cardiac myocyte, and are involved in pathological cardiac function and remodeling. In this paper, we review a link between endoplasmic reticulum homeostasis and microRNA with an emphasis on the impact on stress responses in the cardiovascular system. Key words: ER stress, microRNA, unfolded protein response, endoplasmic reticulum, heart. Les reactions au stress sont importantes en physiologie et en pathologie humaines, et l'incapacite de s'adapter au stress cellulaire mene a la mort de cellules. Afin d'attenuer le stress cellulaire et de retablir l'homeostasie, les cellules, y compris celles du systeme cardiovasculaire, entrainent l'activation de modes d'action de reactions adaptatives au stress. Le reticulum endosplasmique, une composante du reseau reticulaire cellulaire dans les cellules cardiaques, mobilise ce que l'on appelle des reactions adaptatives au stress du reticulum endosplasmique, comme la reponse UPR (pour<< unfolded protein response >>). Les microRNA jouent un role important dans le maintien de l'homeostasie cellulaire et tissulaire, un role central dans la biologie du cardiomyocyte et participent au fonctionnement cardiaque pathologique et au remodelage. Dans cet article, nous etudions un lien entre l'homeostasie du reticulum endoplasmique et les microRNA en mettant l'emphase sur leur incidence sur les reactions au stress dans le systeme cardiovasculaire. [Traduit par la Redaction] Mots-cles: stress du RE, microRNA, reponse UPR, reticulum endoplasmique, creur., Introduction Stress responses are central to human physiology and pathology, and failure to adapt to cellular stress leads to cell death. To mitigate cellular stress and re-establish homeostasis, cardiac cells [...]