10 research outputs found

    Glucosylceramide synthase deficiency in the heart compromises ÎČ1-adrenergic receptor trafficking

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    Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to ÎČ-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of ÎČ1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain ÎČ-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

    The role of the lipid kinase PIKfyve in cardiac remodeling and heart failure : towards new therapeutic perspectives

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    Le remodelage cardiaque est un Ă©lĂ©ment central dans le dĂ©veloppement et la progression de l'insuffisance cardiaque, une cause majeure de morbi/mortalitĂ© dans le monde. Il est dĂ©fini par les changements structurels, mĂ©taboliques et fonctionnels du ventricule gauche qui se manifestent cliniquement par des modifications de taille et de forme du cƓur dans diverses situations pathologiques telles que l'hypertension, l'infarctus du myocarde ou l'obĂ©sitĂ©. Il s'agit donc d'un procĂ©dĂ© complexe et dynamique qui implique une hypertrophie des cardiomyocytes, une production massive de radicaux libres (ROS) et une perte importante de cardiomyocytes par apoptose/nĂ©crose. Cette perte cellulaire induit l'activation des fibroblastes cardiaques et le dĂ©veloppement progressif d'une fibrose interstitielle conduisant Ă  l'insuffisance cardiaque. Mon projet de thĂšse est centrĂ© sur l'Ă©tude du rĂŽle de la kinase PIKfyve dans le remodelage ventriculaire et l'insuffisance cardiaque. PIKfyve est une lipide kinase conservĂ©e au cours de l'Ă©volution qui rĂ©gule de nombreuses fonctions cellulaires fondamentales. Par des approches in vitro et in vivo sur des modĂšles murins d'insuffisance cardiaque, mes travaux de thĂšse identifient PIKfyve et son produit le phosphatidylinositol 5-phosphate comme acteurs clĂ©s de l'altĂ©ration du statut cardiomĂ©tabolique et de l'intĂ©gritĂ© mitochondriale en conditions pathologiques. L'inhibition pharmacologique et Ă©pigĂ©nĂ©tique de l'enzyme prĂ©serve l'intĂ©gritĂ© mitochondriale, rĂ©duit le stress oxydant, l'apoptose cardiomyocytaire, et culmine par l'amĂ©lioration des fonctions cardiaques dans un modĂšle d'insuffisance cardiaque liĂ©e Ă  l'obĂ©sitĂ©. De plus, mes travaux identifient un nouveau mĂ©canisme de rĂ©gulation de la rĂ©ponse au stress cellulaires par PIKfyve qui implique une voie de la dĂ©sacĂ©tylase mitochondriale SIRT3.[...]Cardiac remodeling is a key process in the development and the progression of heart failure, one of the leading causes of morbi/mortality in modern societies. It is defined as a combination of structural, metabolic and functional modifications that clinically manifest as changes in size and shape of the heart, and under the influence of risk factors such as hypertension, myocardial infarction and obesity. Cardiac remodeling is a complex and dynamic process characterized by cardiomyocyte hypertrophy, excessive reactive oxygen species (ROS) generation leading to a massive loss of cardiomyocytes by apoptotic/necrotic cell death. Altogether, these events trigger the differentiation of cardiac fibroblasts into myofibroblasts and the progressive development of interstitial fibrosis leading to cardiac dysfunction. My thesis work focuses on the role of the lipid kinase PIKfyve in cardiac remodeling and heart failure. PIKfyve is the product of an evolutionary conserved single-copy gene and is known to regulate pleiotropic cellular functions. Combining in vitro and in vivo studies in mouse models of cardiac remodeling, my work identifies PIKfyve and its product phosphatidylinositol 5-phosphate as master regulators of the cardiometabolic status and mitochondrial integrity under pathological conditions. Pharmacological or epigenetic inhibition of the enzyme preserves mitochondrial integrity, reduces oxidative stress, myocyte apoptotic death and culminates with improved cardiac function in a mouse model of obesity induced heart failure. These effects are mediated by the mitochondrial deacetylase SIRT3. My work also demonstrates that PIKfyve is a necessary factor in the differentiation of cardiac fibroblasts into myofibroblasts during cardiac remodeling, regulating the TGF-beta/Smad pathway. Altogether, my thesis work unravels a novel role for PIKfyve in myocardial remodeling and paves the way for alternative therapies as a new molecular target for the treatment of cardiometabolic and fibrotic diseases

    Le rÎle de la lipide kinase PIKfyve dans le remodelage ventriculaire et l'insuffisance cardiaque : vers de nouvelles perspectives thérapeutiques

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    Le remodelage cardiaque est un Ă©lĂ©ment central dans le dĂ©veloppement et la progression de l'insuffisance cardiaque, une cause majeure de morbi/mortalitĂ© dans le monde. Il est dĂ©fini par les changements structurels, mĂ©taboliques et fonctionnels du ventricule gauche qui se manifestent cliniquement par des modifications de taille et de forme du cƓur dans diverses situations pathologiques telles que l'hypertension, l'infarctus du myocarde ou l'obĂ©sitĂ©. Il s'agit donc d'un procĂ©dĂ© complexe et dynamique qui implique une hypertrophie des cardiomyocytes, une production massive de radicaux libres (ROS) et une perte importante de cardiomyocytes par apoptose/nĂ©crose. Cette perte cellulaire induit l'activation des fibroblastes cardiaques et le dĂ©veloppement progressif d'une fibrose interstitielle conduisant Ă  l'insuffisance cardiaque. Mon projet de thĂšse est centrĂ© sur l'Ă©tude du rĂŽle de la kinase PIKfyve dans le remodelage ventriculaire et l'insuffisance cardiaque. PIKfyve est une lipide kinase conservĂ©e au cours de l'Ă©volution qui rĂ©gule de nombreuses fonctions cellulaires fondamentales. Par des approches in vitro et in vivo sur des modĂšles murins d'insuffisance cardiaque, mes travaux de thĂšse identifient PIKfyve et son produit le phosphatidylinositol 5-phosphate comme acteurs clĂ©s de l'altĂ©ration du statut cardiomĂ©tabolique et de l'intĂ©gritĂ© mitochondriale en conditions pathologiques. L'inhibition pharmacologique et Ă©pigĂ©nĂ©tique de l'enzyme prĂ©serve l'intĂ©gritĂ© mitochondriale, rĂ©duit le stress oxydant, l'apoptose cardiomyocytaire, et culmine par l'amĂ©lioration des fonctions cardiaques dans un modĂšle d'insuffisance cardiaque liĂ©e Ă  l'obĂ©sitĂ©. De plus, mes travaux identifient un nouveau mĂ©canisme de rĂ©gulation de la rĂ©ponse au stress cellulaires par PIKfyve qui implique une voie de la dĂ©sacĂ©tylase mitochondriale SIRT3. Egalement, mes travaux montrent que la kinase joue un rĂŽle prĂ©pondĂ©rant dans l'activation des fibroblastes cardiaques et le processus de remodelage fibrotique en rĂ©gulant la voie de signalisation TGF-beta/Smad. Dans leur ensemble, mes travaux de thĂšse identifient pour la premiĂšre fois PIKfyve comme nouveau rĂ©gulateur du remodelage cardiaque et ouvrent la voie Ă  des perspectives thĂ©rapeutiques alternatives en proposant PIKfyve comme cible molĂ©culaire pour le traitement des pathologies cardiomĂ©taboliques et fibrotiques.Cardiac remodeling is a key process in the development and the progression of heart failure, one of the leading causes of morbi/mortality in modern societies. It is defined as a combination of structural, metabolic and functional modifications that clinically manifest as changes in size and shape of the heart, and under the influence of risk factors such as hypertension, myocardial infarction and obesity. Cardiac remodeling is a complex and dynamic process characterized by cardiomyocyte hypertrophy, excessive reactive oxygen species (ROS) generation leading to a massive loss of cardiomyocytes by apoptotic/necrotic cell death. Altogether, these events trigger the differentiation of cardiac fibroblasts into myofibroblasts and the progressive development of interstitial fibrosis leading to cardiac dysfunction. My thesis work focuses on the role of the lipid kinase PIKfyve in cardiac remodeling and heart failure. PIKfyve is the product of an evolutionary conserved single-copy gene and is known to regulate pleiotropic cellular functions. Combining in vitro and in vivo studies in mouse models of cardiac remodeling, my work identifies PIKfyve and its product phosphatidylinositol 5-phosphate as master regulators of the cardiometabolic status and mitochondrial integrity under pathological conditions. Pharmacological or epigenetic inhibition of the enzyme preserves mitochondrial integrity, reduces oxidative stress, myocyte apoptotic death and culminates with improved cardiac function in a mouse model of obesity induced heart failure. These effects are mediated by the mitochondrial deacetylase SIRT3. My work also demonstrates that PIKfyve is a necessary factor in the differentiation of cardiac fibroblasts into myofibroblasts during cardiac remodeling, regulating the TGF-beta/Smad pathway. Altogether, my thesis work unravels a novel role for PIKfyve in myocardial remodeling and paves the way for alternative therapies as a new molecular target for the treatment of cardiometabolic and fibrotic diseases

    Role of Perilipins in Oxidative Stress—Implications for Cardiovascular Disease

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    Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia–reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs) are conserved intracellular organelles that enable the safe and stable storage of neutral lipids within the cytosol. LDs are coated with proteins, perilipins (Plins) being one of the most abundant. In this review, we will discuss the interplay between oxidative stress and Plins. Indeed, LDs and Plins are increasingly being recognized for playing a critical role beyond energy metabolism and lipid handling. Numerous reports suggest that an essential purpose of LD biogenesis is to alleviate cellular stress, such as oxidative stress. Given the yet unmet suitability of ROS as targets for the intervention of cardiovascular disease, the endogenous antioxidant capacity of Plins may be beneficial

    Cardiac Cell Exposure to Electromagnetic Fields: Focus on Oxdative Stress and Apoptosis

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    Exposure to electromagnetic fields (EMFs) is a sensitive research topic. Despite extensive research, to date there is no evidence to conclude that exposure to EMFs influences the cardiovascular system. In the present study, we examined whether 915 MHz EMF exposure affects myocardial antioxidative and apoptotic status in vitro and in vivo. No statistically significant difference in the apoptotic cell profile and antioxidant capacity was observed between controls and short-term EMF-exposed mouse cardiomyocytes and H9C2 cardiomyoblasts. Compared with sham-exposed controls, mice subjected to a 915 MHz EMF for 48 h and 72 h had no significant effect on structural tissue integrity and myocardial expression of apoptosis and antioxidant genes. Therefore, these results indicate that short-term exposure to EMF in cardiac cells and tissues did not translate into a significant effect on the myocardial antioxidant defense system and apoptotic cell death

    Glucosylceramide synthase deficiency in the heart compromises ÎČ1-adrenergic receptor trafficking

    No full text
    AIMS : Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function. METHODS AND RESULTS : Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg(–/–) mice). In 9- to 10-week-old hUgcg(–/–) mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg(–/–) mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to ÎČ-adrenergic stimulation was reduced in cardiomyocytes from hUgcg(–/–) mice and that Ugcg knockdown suppressed the internalization and trafficking of ÎČ1-adrenergic receptors. CONCLUSIONS : Our findings suggest that cardiac glycosphingolipids are required to maintain ÎČ-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function
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