Apoptosis and heart failure: mechanisms and therapeutic implications.
01 Jan 2002-American Journal of Cardiovascular Drugs (Springer International Publishing)-Vol. 2, Iss: 1, pp 43-57
TL;DR: Several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo, indicating the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
Abstract: A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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01 Jan 1999
TL;DR: Caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases as discussed by the authors, and they play critical roles in initiation and execution of this process.
Abstract: ■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.
2,685 citations
TL;DR: The nuclear factor kB (NF-kB) comprises a family of transcription factors involved in the regulation of a wide variety of biological responses that play a key role in the development and progression of cancer such as proliferation, migration and apoptosis.
Abstract: The nuclear factor kB (NF-kB) comprises a family of transcription factors involved in the regulation of a wide variety of biological responses. NF-kB plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role in oncogenesis. NF-kB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer such as proliferation, migration and apoptosis. Aberrant or constitutive NF-kB activation has been detected in many human malignancies. In recent years, numerous studies have focused on elucidating the functional consequences of NF-kB activation as well as its signaling mechanisms. NF-kB has turned out to be an interesting therapeutic target for treatment of cancer.
952 citations
Cites background from "Apoptosis and heart failure: mechan..."
...NF-κB also induces the expression of the Inhibitors of Apoptosis (IAPs) [13, 62, 67] and some members of the anti-apoptotic Bcl-2 family [10, 37]....
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TL;DR: The contribution of ceramides in the development of insulin resistance and the complications associated with metabolic diseases is evaluated.
791 citations
TL;DR: It is demonstrated that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes, and a novel mouse model of metabolic cardiomyopathy is established to provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.
Abstract: Inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumulation of cardiotoxic lipid species, and to establish a mouse model of metabolic cardiomyopathy, we generated transgenic mouse lines that overexpress long-chain acyl-CoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane. MHC-ACS mice demonstrate cardiac-restricted expression of the transgene and marked cardiac myocyte triglyceride accumulation. Lipid accumulation is associated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cytochrome c release in transgenic hearts suggest that cardiac myocyte death occurs, in part, by lipid-induced programmed cell death. Taken together, our data demonstrate that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.
731 citations
Cites background from "Apoptosis and heart failure: mechan..."
...In nontransgenic hearts, there is no significant evidence for apoptosis as has been observed by others (48)....
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TL;DR: The role of ceramide and other sphingolipid metabolites in insulin resistance, beta-cell failure, cardiomyopathy, and vascular dysfunction is reviewed, focusing on in vivo studies that identify enzymes controlling sphingoipid metabolism as therapeutic targets for combating metabolic disease.
Abstract: Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic β-cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, β-cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.
516 citations
References
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TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.
Abstract: The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.
15,416 citations
TL;DR: A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins.
Abstract: A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.
8,757 citations
TL;DR: This work has shown that understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic gain.
Abstract: Apoptosis, an evolutionarily conserved form of cell suicide, requires specialized machinery. The central component of this machinery is a proteolytic system involving a family of proteases called caspases. These enzymes participate in a cascade that is triggered in response to proapoptotic signals and culminates in cleavage of a set of proteins, resulting in disassembly of the cell. Understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic gain.
6,924 citations
TL;DR: In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death, and recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases.
Abstract: In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.
6,462 citations
TL;DR: Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival.
Abstract: Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.
5,968 citations