Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change.

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process. Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown. Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week. Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy. Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation.

Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy.

OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS: Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements.

Opposite changes in meteorin-like and oncostatin m levels are associated with metabolic improvements after bariatric surgery.

Bariatric surgery is currently the most effective therapy for type 2 diabetes. However, the mechanisms underlying its beneficial effects remain elusive. Here we studied the effects of bariatric surgery on circulating meteorin-like (Metrnl) and oncostatin m (OSM) levels, two hormones intimately linked to energy homeostasis. Metrnl and OSM levels were assessed at baseline, 6 and 12 months after laparoscopic sleeve gastrectomy (LSG) in 25 patients with obesity, as well as in 33 normal-weight controls. At baseline, patients with obesity showed lower Metrnl and higher OSM levels compared to controls. LSG increased Metrnl and decreased OSM levels, in correlation to improvements in glucose and lipid homeostasis. Our data indicate that LSG conversely modulated Metrnl and OSM levels, and suggest that a dual approach modulating these two molecules might provide a novel strategy for obesity and type 2 diabetes treatment.

C/EBPß is required in pregnancy-induced cardiac hypertrophy.

AIM: Pregnancy is a physiological model of adaptive and reversible heart enlargement, but the molecular mechanisms determining this kind of physiologic cardiac hypertrophy are poorly known. Here, we analyzed the role of the transcription factor C/EBPß in the development of pregnancy-induced cardiac hypertrophy. RESULTS: C/EBPß+/- mice at day 18 of gestation were used as happloinsufficiency model of late pregnancy. We found that C/EBPß expression was specifically increased in hearts from Wt pregnant mice whereas expression of other C/EBP subtypes (α and δ) was not affected by gestation. Pregnancy-induced changes in systemic metabolic and hormonal profiles were not essentially different in Wt versus C/EBPß+/- mice. However, C/EBPß+/- mice developed pregnancy-induced heart hypertrophy to a lower extent relative to Wt mice. Furthermore, hearts from C/EBPß+/- mice have alterations in fatty acid oxidation genes and reductions in the expression levels of glucose transporters that may compromise metabolic cardiac function during pregnancy. Among marker genes of inflammation, interleukin-6 (Il-6) showed a marked differential behavior in C/EBPß+/- pregnant mice: pregnancy strongly induced cardiac Il-6 expression in wt, a phenomenon that did not occur in C/EBPß+/- mice. Moreover, marker genes for M2 macrophages were decreased in C/EBPß+/- pregnant mice and in C/EBPß-/- mice subjected to LPS stimulus. CONCLUSIONS: Here we found that normal levels of C/EBPß are required for hypertrophy development during pregnancy. Events such as the increase in IL-6 in the heart of pregnant mice are prevented in C/EBPß+/- animals. Moreover, C/EBPß controls M2-macrophage gene expression in the heart. Thus, C/EBPß appears as a transcription factor required for cardiac hypertrophy response to gestation.

Fatty acids and cardiac disease: fuel carrying a message.

From the viewpoint of the prevention of cardiovascular disease (CVD) burden, there has been a continuous interest in the detrimental effects of the Western-type high-fat diet for more than half a century. More recently, this general view has been subject to change as epidemiological studies showed that replacing fat by carbohydrate may even be worse and that various polyunsaturated fatty acids (FA) have beneficial rather than detrimental effects on CVD outcome. At the same time, advances in lipid biology have provided insight into the mechanisms by which the different lipid components of the Western diet affect the cardiovascular system. In fact, this still is a rapidly growing field of research and in recent years novel FA derivatives and FA receptors have been discovered. This includes fish-oil derived FA-derivatives with anti-inflammatory properties, the so-called resolvins, and various G-protein-coupled receptors that recognize FA as ligands. In the present review, we will extensively discuss the role of FA and their metabolites on cardiac disease, with special emphasis on the role of the different saturated and polyunsaturated FA and their respective metabolites in cellular signal transduction and the possible implications for the development of cardiac hypertrophy and cardiac failure.

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice.

Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21(-/-) mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21(-/-) mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21(-/-) neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy.

Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1-deficient mice: a role for Sirt1-Mef2 in adult heart.

The deacetylase Sirtuin-1 (Sirt1) is involved in the cardiac hypertrophic responses and cardiac embryo morphogenesis. However, the physiological function of Sirt1 deficiency in the postnatal development of the heart remains to be characterized. The aim of the study was to investigate the relevance of Sirt1 in the development and function of the myocardium. Hearts from Sirt1-deficient mice partially or totally lacking Sirt1 protein activity were analyzed. Loss of Sirt1 activity led to dilated cardiomyopathy in adult hearts, a phenotype accompanied by reduced cardiomyocyte size and the absence of fibrosis. Morphological and functional mitochondrial abnormalities were observed in the adult hearts lacking Sirt1, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Moreover, gene expression analyses revealed that mitochondrial genes were the most affected in Sirt1-deficient mice, showing a reduction in their expression. No overt cardiac dilatation was observed in neonates lacking Sirt1 activity, but first signs of mitochondrial alterations were already present. Immunoblot analyses revealed that Sirt1 is highly expressed in the heart after birth, indicating the importance of Sirt1 in the neonatal period. Finally, Sirt1 deficiency affected the acetylation pattern of the myocyte enhancer factor 2 (Mef2) transcription factors, which are critical for normal heart development and mitochondrial integrity. Collectively, our findings indicate that Sirt1 is essential for the maintenance of cardiac mitochondrial integrity and normal postnatal myocardium development.

Peroxisome proliferator-activated receptors and inflammation: take it to heart.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors acting as key regulators of lipid metabolism as well as modulators of inflammation. The role of PPARalpha and PPARgamma in cardiac ischaemia-reperfusion injury, infarct healing and hypertrophy is the subject of intense research. Due to the later development of PPARdelta-specific ligands, the role of this PPAR isoform in cardiac disease remains to be established. Although many studies point to salutatory effects of PPAR ligands in cardiac disease, the exact molecular mechanism is still largely unsolved. Both the metabolic (via transactivation) and the more recently discovered anti-inflammatory (via transrepression) effects of PPARs are likely to play a role. In this review the reported, and sometimes contradictory, effects of PPAR ligands on ischaemia-reperfusion, infarct healing and cardiac hypertrophy are critically evaluated. In particular the role of inflammation in these disease processes, the ability of PPARs to interfere with pro-inflammatory processes, and the mechanisms of transrepression are discussed. Currently, the significance of PPARs as therapeutic targets in cardiovascular disease is receiving widespread attention. Accordingly, detailed understanding of the mechanisms controlling the activity of these nuclear hormone receptors is essential.

La atorvastatina previene la reducción de los receptores activados por proliferadores peroxisómicos en la hipertrofia cardíaca / Atorvastatin prevents reduction in peroxisome proliferator activated receptors in cardiac hypertrophy

Introducción. La activación del factor nuclear (NF)-kB desempeña un papel clave en el desarrollo de la hipertrofia cardíaca. Aunque se ha demostrado que las estatinas inhiben la hipertrofia cardíaca por su capacidad para reducir la producción de especies reactivas del oxígeno, todavía se desconoce si estos fármacos previenen la activación de NF-kB y si la activación de este factor de transcripción está relacionada con la reducción de la actividad de la vía de los receptores activados por los proliferadores peroxisómicos (PPAR). Material y método. Este estudio ha examinado el papel de la atorvastatina sobre la actividad NF-kB y los PPAR en la hipertrofia cardíaca inducida por sobrecarga de presión. Resultados. Los resultados indican que la atorvastatina inhibe la hipertrofia cardíaca y previene la reducción de las concentraciones de proteína de PPAR α y β/δ. Además, el tratamiento con atorvastatina evitó la activación de NF-kB durante el desarrollo de la hipertrofia cardíaca, reduciendo la asociación proteína-proteína entre los PPAR y la subunidad p65 de NF-kB. Conclusiones. Los resultados obtenidos indican que la interacción entre NF-kB y los proliferadores peroxisómicos puede intereferir la capacidad de transactivación de los últimos, y provocar una reducción en la expresión de sus genes diana implicados en el metabolismo de los ácidos grasos. Estos cambios se evitaron con atorvastatina (AU)

Introduction. Nuclear factor (NF)-kB signalling pathway plays a pivotal role in cardiac hypertrophy. Although statins have been reported to inhibit cardiac hypertrophy by reducing the generation of reactive oxygen species, it is not yet known whether statins prevent NF-kB activation and whether this effect can be related to the reduction in the peroxisome proliferator-activated receptor (PPAR) pathway. Material and method. In this study, we examined the role of atorvastatin on NF-kB activity and PPAR signaling in pressure overload-induced cardiac hypertrophy. Results. Our findings indicate that atorvastatin inhibits cardiac hypertrophy and prevents the fall in protein levels of PPARα and PPARβ/δ. Furthermore, atorvastatin treatment avoided NF-kB activation during cardiac hypertrophy, by reducing the protein-protein association between these PPAR subtypes and the p65 subunit of NF-kB. Conclusions. These findings indicate that negative cross-talk between NF-kB and PPAR may interfere in the transactivation capacity of the latter, leading to a fall in the expression of genes involved in fatty acid metabolism, and that these changes are prevented by atorvastatin (AU)

D) ¿Modula el metabolismo lipídico del miocardio la hipertrofia cardíaca? / No disponible

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