Resveratrol Improves Survival, Hemodynamics and Energetics in a Rat Model of Hypertension Leading to Heart Failure

Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening −34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium–dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Myopathie métabolique généralisée dans l'insuffisance cardiaque (facteurs impliqués et conséquences fonctionnelles)

Les patients souffrant d'insuffisance cardiaque (IC) se plaignent d'une incapacité à l'exercice physique. Les travaux précédents dans notre laboratoire ont montré une myopathie métabolique généralisée dans l'IC. Le caractère généralisé de la myopathie dans l'IC suggère l'implication de facteurs systémiques. Dans ce travail, nous avons étudié l'implication éventuelle de deux agents [nitrique oxyde (NO) produit par la nitrique oxyde synthase endothéliale (NOSe) et l'angiotensine II (AngII)] considérablement altérés dans l'IC et dans le développement de la myopathie métabolique généralisée. Les résultats obtenus suggèrent que l'action bénéfique des inhibiteurs de l'enzyme de conversion sur le profil métabolique musculaire nécessite une diminution de la " post-charge " cardiaque. Nous avons également montré le rôle important du NO produit par la NOSe dans le métabolisme énergétique du muscle squelettique oxydatif ainsi que dans le maintien de la capacité physique de l'organismePatients suffering from heart failure (HF) complain of intolerance to exercise. Previous work in our laboratory has shown that HF (by aortic stenosis) in rats is associated with a myopathy that alters energy metabolism in different muscles. The generalized character of the metabolic myopathy in HF suggests that some systemic factors could be involved. Angiotensin II (AngII) and nitric oxide produced by endothelial nitric oxide synthase (eNOS) are two systemic factors whose production is greatly changed in heart failure. Angiotensin converting enzyme inhibitors (IEC) are known to improve the mortality and morbidity rates in HF. Our results have shown that the beneficial effect of IEC on the metabolic myopathy is probably associated with a reduction in afterload. We have shown that eNOS deficiency induces a significant reduction of mitochondrial oxidative capacity specifically in slow-twitch muscle and we have demonstrated that eNOS is necessary for maintaining normal physical activity.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Rôle de la cytoarchitecture dans la signalisation énergétique du cœur de souris

La cellule cardiaque requiert un apport énergétique conséquent qui exige une production et un transfert énergétiques efficaces. Si la production de l énergie dépend essentiellement des propriétés intrinsèques des mitochondries, il semblerait que l efficacité du transfert d énergie du site de production vers les sites consommateurs (ATPases) pourrait être liée à l architecture spécifique du cardiomyocyte qui conduit à une organisation spatiale singulière des structures internes (mitochondries, réticulum sarcoplasmique, myofilaments). Pour comprendre ce qui lie la cytoarchitecture, la compartimentation cellulaire et la fonction contractile, il a été entrepris d étudier l architecture cellulaire et la signalisation énergétique de cardiomyocytes au cours du processus de maturation de la cytoarchitecture et dans un modèle présentant une désorganisation des structures intracellulaires. La première partie de ce travail, réalisée durant le développement postnatal de la souris, a permis de démontré qu il existe une synchronisation parfaite entre la mise en place de la cytoarchitecture et la maturation fonctionnelle du transfert d énergie par canalisation directe des nucléotides adényliques entre les mitochondries et les ATPases. Si cette étude apporte un élément qui tendrait à démontrer l implication de l architecture cellulaire dans l efficacité des transferts d énergie, elle a également mis en avant la maturation très précoce de l énergétique cellulaire. La mitochondrie faisant partie intégrante de cette architecture et étant modelée par des mécanismes de fusion et de fission, la deuxième étape de ce travail de thèse a consisté à étudier l implication de la morphologie mitochondriale dans l énergétique du cardiomyocyte. Il a ainsi été montré que, chez la souris, la diminution d expression de la protéine OPA1, impliquée dans la fusion mitochondriale, conduit à des perturbations de la morphologie mitochondriale qui n affectent pas la fonction intrinsèque mitochondriale mais qui altèrent le système de canalisation directe entre les mitochondries et les ATPases des myofilaments. De manière générale, ces résultats démontrent clairement une dépendance des transferts d énergie à l architecture cellulaire spécifique de la cellule musculaire cardiaque.The cardiac cell function requires a large amount of energy and therefore needs a high efficiency of energetic production and energetic transfer. While the energy production depends on the intrinsic properties of the mitochondria, it appears that the efficiency of energetic transfers from the main producers (mitochondria) to consumers (ATPases) could be related to the specific architecture of the cardiomyocyte, which ensures a unique spatial organization of internal structures (mitochondria, sarcoplasmic reticulum, myofilaments). In order to reveal the role of mitochondrial network organization in cardiac energy metabolism, we studied the cellular architecture and the energetic signalling of cardiomyocytes in the process of maturation of the cytoarchitecture and in a model which exhibits a perturbation of the mitochondrial dynamics. The first part of this work, which was performed during postnatal development of the mouse, showed the perfect synchronisation between the establishment of the cytoarchitecture and the maturation of the transfer of energy by direct channelling of adenine nucleotides between mitochondria and ATPases. While this study provides an element which would demonstrate the involvement of cellular architecture in the efficiency of energy transfer, it also highlighted the very early maturation of the energetic system of the cell. Knowing that the mitochondria are an integral part of the cell architecture and that the mitochondrial network is controlled by fusion and fission mechanisms, the second step of this work consisted in investigating the involvement of mitochondrial dynamics in cardiomyocyte energetics. Our work has shown that a decrease in expression of OPA1, a protein responsible for mitochondrial fusion, leads to disruption of mitochondrial morphology which does not affect intrinsic mitochondrial function but affects the direct channelling of ATP and ADP between mitochondria and ATPases of the myofilaments. Overall, these results clearly demonstrate that energy transfer in cardiomyocytes strictly depends on specific cellular architecture.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Transcriptional control of mitochondrial biogenesis. The central role of PGC-1alpha.: Transcriptional control of mitochondrial biogenesis

International audienceAlthough the concept of energy starvation in the failing heart was proposed decades ago, still very little is known about the origin of energetic failure. Recent advances in molecular biology have started to elucidate the transcriptional events governing mitochondrial biogenesis. In particular a great step forwards was taken with the discovery that peroxisome proliferator-activated receptor gamma co-activator (PGC-1alpha) is the master regulator of mitochondrial biogenesis. The molecular mechanisms underlying the downregulation of PGC-1α and the consequent decrease in mitochondrial function in heart failure are, however, still poorly understood. Indeed, the main pathways involved in mitochondrial biogenesis are thought to be up- rather than down-regulated in pathological hypertrophy and heart failure. The current review summarizes recent advances in this field and is restricted to the heart when cardiac data is available