Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscle

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles

Facteurs prédictifs d'insuffisance rénale aiguë après chirurgie cardiaque

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Anticoagulation post-opératoire immédiate par héparine de bas poids moléculaire après un remplacement valvulaire prothétique mécanique

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Transmuralité de la fonction mitochondriale myocardique dans le coeur sain et hypertrophique

Le ventricule gauche de mammifère, à l état basal, présente une hétérogénéité transmurale en termes de contrainte pariétale et de contractilité. En effet dans le subendocarde des mammifères, il existe une contractilité et une contrainte pariétale plus importantes. La fonction mitochondriale, dans le subendocarde et le subépicarde du ventricule gauche, a été peu décrite jusque-là.L objectif de ce travail a été d étudier les capacités oxydatives mitochondriales dans les différentes couches de la paroi ventriculaire gauche à l état basal, mais également en présence d une hypertrophie ventriculaire gauche induite par augmentation de la postcharge. Nous avons également analysé la production de stress oxydant mitochondrial et le système anti-oxydant.Nous avons observé, à l état basal dans le subendocarde, une diminution des capacités oxydatives des complexes de la chaîne respiratoire mitochondriale par rapport au subépicarde. Ce gradient énergétique est associé à des gradients transcriptionnel et post-transcriptionnel de l oxyde nitrique aboutissant à une augmentation de la production d oxyde nitrique dans le subendocarde. Cette augmentation de l oxyde nitrique dans le subendocarde via l oxyde nitrique synthétase 1, induit une inhibition des complexes de la chaîne respiratoire. Malgré l augmentation de la production de stress oxydant par les mitochondries dans le subendocarde, l activation de la biogenèse mitochondriale et du système anti-oxydant permet de maintenir l intégrité transmurale du myocarde, avec absence de sensibilisation du pore de transition de perméabilité mitochondriale dans la paroi ventriculaire gauche à l état basal.L hypertrophie ventriculaire gauche induite par une augmentation de la postcharge, est associée à une altération des capacités oxydatives mitochondriales dans le subendocarde, et de manière plus prononcée dans le subépicarde, aboutissant à une diminution du gradient transmural énergétique. Cette altération du gradient transmural est accompagnée d une augmentation de la production de ROS par la mitochondrie dans le subendocarde et le subépicarde. L activation du système anti-oxydant mais également de la sirtuine3, permet de maintenir les fonctions systolique et diastolique du cœur.En conclusion, il existe un gradient transmural des capacités oxydatives mitochondriales qui diminuent du subépicarde vers le subendocarde, dans la paroi ventriculaire gauche à l état basal. En présence d une hypertrophie ventriculaire gauche, ces capacités oxydatives diminuent, avec une atténuation de ce gradient. L augmentation de la production de stress oxydant mitochondrial est accompagnée d une activation du système anti-oxydant, permettant le maintien de la fonction ventriculaire.The myocardium is nonuniform with respect to its structure and function. Mitochondria are the main energy powerhouses of cells and are major source of reactive oxygen species. The mitochondrial function in the different layers of the left ventricular wall has been poorly described in the normal heart and in mild left ventricular hypertrophy. Nitric oxide has highly specific signaling pathways in the heart which is promoted by the compartmentalization of nitric oxide synthetases in the myocytes. The purpose of this study was to determine whether a left ventricular transmural gradient is present in myocardium and to determine how this gradient affects mitochondrial function. Furthermore we characterized the changes that occur in various left ventricular layers during the adaptation of mitochondrial function from the basal state to mild left ventricular hypertrophy.Basal nitric oxide synthetase 1 mRNA expression was significantly higher in the subendocardium and was associated with 2-fold higher nitric oxide production in the subendocardium compared with the subepicardium. Increased nitric oxyde in the subendocardium inhibited the mitochondrial respiratory complexes, which subsequently increased mitochondrial hydrogen peroxide and superoxide anion production in the subendocardium. This overproduction of reactive oxygen species was associated with an activation of antioxidant defence and mitochondrial biogenesis in the subendocardium. Finally, nitric oxide production and the balance between reactive oxygen species production and antioxidant activity maintained constant the sensitivity of the mitochondrial permeability transition pore in the left ventricular wall.Mild left ventricular hypertrophy reduced maximal oxidative capacity, increased mitochondrial hydrogen peroxide production, and increased sirtuin 3 and Cu/Zn-superoxide dismutase expression in the subendocardium and subepicardium, respectively. The mitochondrial biogenesis in the left ventricular wall was unchanged. The transmural energetic gradient for complex IV activity was significantly lower in cardiac hypertrophy.In summary, nitric oxide synthetase 1-derived nitric oxide is elevated in the subendocardium of the left ventricle at basal state and induces a balanced inhibition of the mitochondrial function. The transition to mild cardiac hypertrophy is characterized by alterations in the mitochondrial oxidative capacity and by increased oxidative stress. Increased sirtuin 3 expression and antioxidant defence systems might contribute to protection against maladaptive left ventricular hypertrophy.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Variations péri-opératoires du fibrinogène et prise en charge du saignement post-opératoire

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Prokineticin receptor-1-dependent paracrine and autocrine pathways control cardiac tcf21(+) fibroblast progenitor cell transformation into adipocytes and vascular cells

International audienceCardiac fat tissue volume and vascular dysfunction are strongly associated, accounting for overall body mass. Despite its pathophysiological significance, the origin and autocrine/paracrine pathways that regulate cardiac fat tissue and vascular network formation are unclear. We hypothesize that adipocytes and vasculogenic cells in adult mice hearts may share a common cardiac cells that could transform into adipocytes or vascular lineages, depending on the paracrine and autocrine stimuli. In this study utilizing transgenic mice overexpressing prokineticin receptor (PKR1) in cardiomyocytes, and tcf21ERT-cre(TM)-derived cardiac fibroblast progenitor (CFP)-specific PKR1 knockout mice (PKR1 (tcf-/-)), as well as FACS-isolated CFPs, we showed that adipogenesis and vasculogenesis share a common CFPs originating from the tcf21(+) epithelial lineage. We found that prokineticin-2 is a cardiomyocyte secretome that controls CFP transformation into adipocytes and vasculogenic cells in vivo and in vitro. Upon HFD exposure, PKR1 (tcf-/-) mice displayed excessive fat deposition in the atrioventricular groove, perivascular area, and pericardium, which was accompanied by an impaired vascular network and cardiac dysfunction. This study contributes to the cardio-obesity field by demonstrating that PKR1 via autocrine/paracrine pathways controls CFP-vasculogenic- and CFP-adipocyte-transformation in adult heart. Our study may open up new possibilities for the treatment of metabolic cardiac diseases and atherosclerosis

A prokineticin-driven epigenetic switch regulates human epicardial cell stemness and fate

International audienceEpicardial adipose tissues (EAT) and vascular tissues may both belong to the mesoepithelial lineage that develops from epicardium-derived progenitor cells (EPDCs) in developing and injured hearts. Very little is known of the molecular mechanisms of EPDC contribution in EAT development and neovascularization in adult heart, which the topic remains a subject of intense therapeutic interest and scientific debate. Here we studied the epigenetic control of stemness and anti-adipogenic and pro-vasculogenic fate of hEPDCs, through investigating an angiogenic hormone, prokineticin-2 (PK2) signaling via its receptor PKR1. We found that hEPDCs spontaneously undergoes epithelial-to-mesenchymal transformation (EMT), and are not predestined for the vascular lineages. However, PK2 via a histone demethylase KDM6A inhibits EMT, and induces asymmetric division, leading to self-renewal and formation of vascular and epithelial/endothelial precursors with angiogenic potential capable of differentiating into vascular smooth muscle and endothelial cells. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes (Flk-1 and SM22α) involved in vascular lineage commitment and maturation. In PK2-mediated anti-adipogenic signaling, KDM6A stabilizes and increases cytoplasmic β-catenin levels to repress PPARγ expression and activity. Our findings offer additional molecular targets to manipulate hEPDCs-involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases. This article is protected by copyright. All rights reserved