Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autophagy is a major mechanism for degrading long-lived cytosolic proteins and the only known pathway for degrading organelles. Autophagy is activated by many forms of stress, including nutrient and energy starvation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and infections. Although autophagy recycles amino acids and fatty acids to produce energy and removes damaged organelles, thereby playing an essential role in cell survival, inappropriate activation of autophagy leads to cell death. In the heart, activation of autophagy can be observed in response to nutrient starvation, ischemia/reperfusion, and heart failure. In this review, the signaling mechanism and the functional significance of autophagy during myocardial ischemia and reperfusion are discussed.
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PMID:The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. 1762 77

Famine edema was produced experimentally in 34 normal men who lost a quarter of their body weight while subsisting for 6 months on a European type of semi-starvation diet. The ratio of extracellular water to cellular tissue was roughly doubled. Their clinical state closely resembled that seen in Europe in 1945. There were no signs of renal or cardiac failure. The plasma protein concentration fell only slightly and the A/G ratio remained within normal limits. The venous pressure was roughly 50 per cent below normal. Data from the field lend support to these indications that famine edema is not simply a result of hypoproteinemia or of renal or cardiac failure. It is concluded that there is a dynamic nonequilibrium state of the capillary wall and, accordingly, calculations from equilibrium equations are inadmissible.
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PMID:Famine Edema and the Mechanism of Its Formation. 1775 25

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggregates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy has an essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.
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PMID:Recycle or die: the role of autophagy in cardioprotection. 1835 58

Although 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 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-1alpha 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 are available.
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PMID:Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. 1843 Jul 51

Clinical heart failure results from the cumulative loss of functioning myocardium from any cause. At the cellular level, cardiac myocytes die from three causes, individually or in combination: Necrosis occurs when external conditions are not sufficient to sustain minimal cellular functions, as with ischemia, and there is a general and unorganized breakdown of cell organelles, engendering an inflammatory response that may have harmful collateral tissue effects. Apoptosis, or cell suicide, occurs when specific external or internal conditions provoke a highly structured sequence of events to shut down cellular functions and remove the cell, with minimal consequences to surrounding tissue. Autophagy is a normal response to cell starvation that is induced under conditions of chronic metabolic or other stress. Current therapeutics, such as early myocardial revascularization after myocardial infarction, are focused exclusively upon minimizing cardiac myocyte necrosis and may even contribute to secondary apoptosis and autophagy. This review explores possible approaches to bring cardiac myocytes that are destined to die, back to life, i.e., cellular resuscitation. Two pro-apoptotic proteins in particular, Bnip3 and Nix, are transcriptionally upregulated specifically in response to myocardial ischemia and pathological hypertrophy and have been examined as therapeutic targets. In Bnip3 and Nix genetic mouse models, prevention of cardiac myocyte apoptosis in ischemic and hemodynamically overloaded hearts salvaged myocardium, minimized late ventricular remodeling, and enhanced ventricular performance. Cardiomyocyte resuscitation by preventing programmed cell death shows promise as an additive approach to minimizing necrosis for long-term prevention of heart failure.
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PMID:The rationale for cardiomyocyte resuscitation in myocardial salvage. 1856 79

Murine models of starvation-induced muscle atrophy demonstrate that reduced protein kinase B (AKT) function upregulates the atrophy-related gene atrogin-1/MAFbx (atrogin). The mechanism involves release of inhibition of Forkhead transcription factors, namely Foxo1 and Foxo3. Elevated atrogin mRNA also corresponds with elevated TNF in inflammatory catabolic states, including cancer and chronic heart failure. Exogenous tumor necrosis factor (TNF) increases atrogin mRNA in vivo and in vitro. We used TNF-treated C2C12 myotubes to test the hypothesis that AKT-Foxo1/3 signaling mediates TNF regulation of atrogin mRNA. Here we confirm that exposure to TNF increases atrogin mRNA (+125%). We also confirm that canonical AKT-mediated regulation of atrogin is active in C2C12 myotubes. Inhibition of phosphoinositol-3 kinase (PI3K)/AKT signaling with wortmannin reduces AKT phosphorylation (-87%) and increases atrogin mRNA (+340%). Activation with insulin-like growth factor (IGF) increases AKT phosphorylation (+126%) and reduces atrogin mRNA (-15%). Although AKT regulation is intact, our data suggest it does not mediate TNF effects on atrogin. TNF increases AKT phosphorylation (+50%) and stimulation of AKT with IGF does not prevent TNF induction of atrogin mRNA. Nor does TNF appear to signal through Foxo1/3 proteins. TNF has no effect on Foxo1/3 mRNA or Foxo1/3 nuclear localization. Instead, TNF increases nuclear Foxo4 protein (+55%). Small interfering RNA oligos targeted to two distinct regions of Foxo4 mRNA reduce the TNF-induced increase in atrogin mRNA (-34% and -32%). We conclude that TNF increases atrogin mRNA independent of AKT via Foxo4. These results suggest a mechanism by which inflammatory catabolic states may persist in the presence of adequate growth factors and nutrition.
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PMID:TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling. 1870 53

During ischemia and heart failure, myocardial cells suffer for chronic energy starvation resulting in metabolic and contractile dysfunction. In normal conditions fatty acids, glucose, and lactate are the principal oxidative fuels in myocardium, while amino acids serve a minor role as an oxidative fuel. However, in pathological conditions, myocardial uptake of several amino acids increases significantly as a consequence of a metabolic remodelling. Amino acids are involved in a variety of key biochemical and physiological activities, that counteract the deleterious cellular effects of reduced oxygen availability. Several amino acids are a direct source of substrate for energy production, and they modulate the activity of some enzymes involved in the glucose metabolism. They increase contractile performance both in isolated animal and human myocardium. Furthermore, amino acids improve the oxidative stress counteracting the action of radical oxygen species, being either precursors of glutathione synthesis, or of substrate of nitric oxide biosynthesis; they act on endothelial function and increase protein synthetic efficiency of myocardial cells by regulating gene expression and modulating hormonal activity. An amount of studies have demonstrated that amino acids administration, on patients with ischemic heart disease and heart failure, can improve several clinical endpoints. Here, we present an overview of the principal effects of the most experienced amino acids and of amino acid derivatives on ischemia and heart failure.
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PMID:The role of amino acids in the modulation of cardiac metabolism during ischemia and heart failure. 1899 76

Parenteral iron is toxic to many species but, because the uptake of iron from the diet is regulated in the intestine, acute intoxication is not seen under natural conditions. Chronic ingestion of large amounts of absorbable iron in the diet can lead to the storage of iron in the liver in many species, including humans. The excess iron is stored within hepatocytes as haemosiderin and can be quantitatively assessed by liver biopsy or at necropsy using special stains such as Perls iron stain and/or biochemical tests. Iron may also be found within the Kupffer cells in the liver and the macrophage cells of the spleen especially where concurrent diseases are present such as haemolytic anaemia, septicaemia, neoplasia and starvation. Iron accumulation in the liver, also known as haemosiderosis, may not always be associated with clinical disease although in severe cases hepatic damage may occur. It is probable that concurrent disease conditions are largely responsible for the degree and nature of the pathological changes described in most cases of haemosiderosis. In some human individuals there may be a genetic predisposition to iron storage disease, haemochromatosis, associated with poor regulation of iron uptake across the intestine. In severe cases iron pigment will be found in the liver, spleen, gut wall, kidney and heart with subsequent development of ascites, heart failure and multisystem pathology. Clinical disease associated with accumulation of iron in the liver, and other tissues, has been reported in many species of bird although it is most commonly reported in Indian hill mynas ( Gracula religiosa ) and toucans ( Ramphastos sp ). It is likely that the tolerance to the build up of tissue iron varies in individual species of bird and that the predominant predisposing factors may differ, even within closely related taxonomic groups.
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PMID:Iron storage diseases in birds. 1918 82

Autophagy, a highly conserved cellular mechanism wherein various cellular components are broken down and recycled through lysosomes, occurs constitutively in the heart and may serve as a cardioprotective mechanism in some situations. It has been implicated in the development of heart failure and is up-regulated following ischemia-reperfusion injury. Autophagic flux, a measure of autophagic vesicle formation and clearance, is an important measurement in evaluating the efficacy of the pathway, however, tools to measure flux in vivo have been limited. Here, we describe the use of monodansylcadaverine (MDC) and the lysosomotropic drug chloroquine to measure autophagic flux in in vivo model systems, specifically focusing on its use in the myocardium. This method allows determination of flux as a more precise measure of autophagic activity in vivo much in the same way that Bafilomycin A(1) is used to measure flux in cell culture. MDC injected 1 h before sacrifice, colocalizes with mCherry-LC3 puncta, validating its use as a marker of autophagosomes. This chapter provides a method to measure autophagic flux in vivo in both transgenic and nontransgenic animals, using MDC and chloroquine, and in addition describes the mCherry-LC3 mouse and the advantages of this animal model in the study of cardiac autophagy. Additionally, we review several methods for inducing autophagy in the myocardium under pathological conditions such as myocardial infarction, ischemia/ reperfusion, pressure overloading, and nutrient starvation.
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PMID:Novel methods for measuring cardiac autophagy in vivo. 1921 14

Autophagy is a catabolic process through which damaged or long-lived proteins, macromolecules, or organelles are recycled by using lysosomal degradation machinery. Although the occurrence of autophagy in several cardiac diseases including ischemic or dilated cardiomyopathy, heart failure, hypertrophy, and during ischemia/reperfusion injury have been reported, the exact role of autophagy in these diseases is not known. Emerging studies indicate that oxidative stress in cellular system could induce autophagy, and oxidatively modified macromolecules and organelles can be selectively removed by autophagy. Mild oxidative stress-induced autophagy could provide the first line of protection against major damage like apoptosis and necrosis. Cardiac-specific loss of Atg5, an autophagic gene involved in the formation of autophagosome, causes cardiac hypertrophy, left ventricular dilation, and contractile dysfunction. Recently, it was revealed that Atg4, another autophagic gene involved in the formation of autophagosomes, is controlled through redox regulation under the condition of starvation-induced autophagy. In this review, we discuss the function of autophagy in association with oxidative stress and redox signaling in the remodeling of cardiac myocardium. Further research is needed to explore the possibilities of redox regulation of other autophagic genes and the role of redox signaling-mediated autophagy in the heart.
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PMID:Autophagy, redox signaling, and ventricular remodeling. 1932 38


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