Apoptosis in heart and skeletal muscle.

Apoptosis, or programmed cell death, is now recognized to be an important cellular event during normal development and in the progression of specific diseases. Apoptosis can be triggered by stimuli initiating outside of the cell, or within the mitochondria, leading to the activation of caspases and subsequent cell death. Although apoptosis has been widely studied in a variety of tissues over the last 5 years, skeletal muscle and heart have been relatively ignored in this regard. Research on apoptosis in cardiac muscle has recently taken on a higher profile as the recognition emerges that it may be an important contributor to specific cardiac pathologies, particularly in response to ischemia-reperfusion in which reactive oxygen species are formed. In skeletal muscle, very few studies have been done under specific physiological (e.g., exercise) and pathophysiological (e.g., dystrophies, denervation, myopathies) conditions. Skeletal muscle is unique in that it is multi-nucleated, and evidence suggests that it can undergo individual myonuclear apoptosis as well as complete cell death. This review discusses the basic cellular mechanisms of apoptosis, as well as the current evidence of this process in cardiac and skeletal muscle. The need for more work in this area is highlighted, particularly in exercise and training.     

The pathogenesis of inflammatory muscle diseases: on the cutting edge among the environment,the genetic background,the immune response and the dysregulation of apoptosis

Inflammatory muscle diseases (IMD), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. The etiology of IMD is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response. Cellular infiltrates found in the muscle provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. The pathologic differences found between PM and DM indicate a different role played by cell-mediated and humoral immune alterations. It is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. Apoptosis, or programmed cell death, is a complex process that plays a key role in many physiological events. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, and evidence of a lack of apoptosis in IMD suggests a failure of apoptotic clearance of inflammatory cells playing a role in the maintenance of chronic cytotoxic muscle fibre damage. Most likely, the failure of apoptosis seems to be the main hallmark of the pathogenesis of IMD.     

Alloreactivity and apoptosis in graft rejection and transplantation tolerance

Weissmann wrote as early as 1889 that higher organisms contain within themselves the germs of death [1]. However, the term, programmed cell death, or apoptosis as it is now known, was defined much later [2]. Thus, it was long recognized that damaged and old cells are eliminated within the body, but the underlying mechanisms are only now beginning to emerge. Apoptosis appears central to the process of negative selection of developing T-cells in the thymus. In regard to organ transplantation, apoptosis contributes to graft rejection and the establishment of graft tolerance. Thus, understanding the regulatory mechanisms of apoptosis may help establish a new protocol for the induction of transplantation tolerance.     

Detection of apoptosis using in situ markers for DNA strand breaks in the failing human heart. Fact or epiphenomenon?

The role of apoptosis and the methods used for its detection in failing human hearts are controversial. Recent data have challenged the hypothesis that in situ markers for DNA strand breaks mirror apoptotic (TUNEL and Taq in situ ligation assay) and/or necrotic (Pfu in situ ligation assay) cell death, and thus provide evidence that apoptotic cell loss contributes to the progression of heart failure. Experimental data cast doubt not only upon the specificity of the TUNEL technique but also the Taq in situ ligation assay as a reliable method for the detection of apoptotic cell death and provide compelling new evidence that the occurrence of cardiomyocyte cell death as defined by the detection of DNA strand breaks using either TUNEL or Taq and Pfu in situ ligation assays is an epiphenomena that is not related to the evolution of heart failure. Cardiomyocyte positivity for in situ markers of DNA strand breaks is a feature of hypertrophic cardiomyopathic hearts, irrespective of the underlying pathology or the presence or absence of heart failure. These data raise concerns regarding the extent of apoptosis in cardiomyopathy and the contribution of this process to the progression of heart failure.     

Cell death in the thymus--it' s all a matter of contacts

Apoptosis, or programmed cell death, plays a critical role in shaping the T cell repertoire, deleting unproductive as well as potentially autoreactive T cells. Our understanding of how thymocyte apoptosis is regulated is continually evolving, as new essential modulators of this process are discovered. A conundrum that remains, however, is how signaling through essentially the same receptors and cascades evokes distinct biological responses: death by neglect, positive or negative selection. We hypothesize that the immunological synapse (IS) may be critical to transducing survival signals during thymocyte development, and suggest that factors affecting IS assembly may also influence T cell selection.     

Viruses and apoptosis

Apoptosis, or programmed cell death, is essential in development and homeostasis in multi-cellular organisms. It is also an important component of the cellular response to injury. Many cells undergo apoptosis in response to viral infection, with a consequent reduction in the release of progeny virus. Viruses have therefore evolved multiple distinct mechanisms for modulating host cell apoptosis. Viruses may interfere with either the highly conserved 'effector' mechanisms of programmed cell death or regulatory mechanisms specific to mammalian cells. In addition to conferring a selective advantage to the virus, the capacity to prevent apoptosis has an essential role in the transformation of the host cell by oncogenic viruses. This article provides a focussed review of apoptosis and illustrates how the study of viruses has informed our understanding of this process. Selected mechanisms by which viral gene products interfere with cell death are discussed in detail and used to illustrate the general principles of the interactions between viruses and apoptosis.     

Trypanosoma cruzi infection and nuclear factor kappa B activation prevent apoptosis in cardiac cells

Studies of cardiac pathology and heart failure have implicated cardiomyocyte apoptosis as a critical determinant of disease. Recent evidence indicates that the intracellular protozoan parasite Trypanosoma cruzi, which causes heart disease in chronically infected individuals, impinges on host apoptotic pathways in a cell type-dependent manner. T. cruzi infection of isolated neuronal cells and cardiomyocytes protects against apoptotic cell death, whereas apoptosis is triggered in T cells in T. cruzi-infected animals. In this study, we demonstrate that the ability of T. cruzi to protect cardiac cells in vitro from apoptosis triggered by a combination of tumor necrosis factor alpha and serum reduction correlates with the presence of intracellular parasites and involves activation of host cell NF-kappaB. We further demonstrate that the apoptotic block diminishes activation of caspase 3. The ability of T. cruzi to prevent apoptosis of infected cardiomyocytes is likely to play an important role in establishment of persistent infection in the heart while minimizing potential damage and remodeling that is associated with cardiomyocyte apoptosis in cardiovascular disease.     

Hyperosmotic activation of the CD95 death receptor system

Apoptosis is characterized by cell shrinkage, nuclear condensation, DNA fragmentation and apoptotic body formation. These features distinguish apoptosis from other types of cell death, such as necrosis. Whereas some signs of apoptosis, such as externalization of phosphatidylserine, altered mitochondrial function or activation of caspases are cell type- and death signal-dependent, apoptotic cell volume decrease (AVD) is an early and ubiquitous event and little is known about the signalling events, which are localized upstream of the plasma membrane transport steps leading to AVD and the proapoptotic events, which are induced by osmolyte loss and cell shrinkage. In hepatocytes hyperosmotic shrinkage sensitizes the cells towards CD95 ligand-induced apoptosis by activating the CD95 system. This complex process with a NADPH oxidase-derived reactive oxygen species signal as an important upstream event, allows via Yes, JNK and epidermal growth factor-receptor activation for CD95 tyrosine phosphorylation as a prerequisite for CD95 targeting to the plasma membrane and formation of the death inducing signalling complex. Other covalent modifications such as CD95-tyrosine-nitration or CD95-serine/threonine-phosphorylation can interfere with the CD95 activation process. The findings not only provide a mechanistic explanation for the high susceptibility of dehydrated cells for apoptosis, but also give insight into the role of AVD.     

Cardiac remodeling and failure: from molecules to man (Part I).

The process of heart failure appears to be a common and coordinated response to cardiac injury and dysfunction. The contemporary mechanistic viewpoint that predictable, shared, highly regulated events underlie the complex heart failure process implies that an improved understanding of these mechanisms is fundamental to the advancement of cardiovascular biology and the subsequent development of targeted, effective treatment strategies for patients with congestive heart failure (CHF). Cardiac remodeling (CR) is the restructuring and reshaping of the heart that underlies heart failure progression. CR is a major determinant of the clinical course of CHF, irrespective of its etiology. The traditional concepts of cellular remodeling in the failing heart are based on well-established data indicating characteristic alterations in cell size, shape, and the ability to perform contractile work. The role of programmed cell death and the exciting possibility of cardiomyocyte regeneration are areas of intense investigation. Notably, the accumulating data in both animal and human hearts suggesting cardiomyocyte regeneration and renewal indicate that cellular remodeling is a complex and dynamic process that is not completely understood. For the development of new treatments to regenerate and restore failing myocardium, the possibilities offered by controlling cell death and enhancing cell renewal as a therapeutic target are unprecedented. Based on a critical review of the available literature, the traditional concepts and mechanisms describing the regulation of remodeling are largely inadequate. The neurohormonal (RAAS and adrenergic systems) and innovative cytokine hypothesis (TNF-alpha and others) of remodeling and failure do not account for all the cellular and molecular changes that result in the progression of CHF. Given that these contemporary concepts serve as the basis for the majority of our current heart failure treatments, it is not surprising that CHF is an emerging epidemic in our society. To define new therapeutic targets and to control the process of remodeling, novel biomolecules and mechanisms for the coordinated control of CR must be further defined.     

Molecular mechanisms of liver injury: Apoptosis or necrosis

Hepatic apoptosis is thought of as a prevalent mechanism in most forms of liver injury. However, the role of hepatic apoptosis is often intermixed with the cellular necrosis. It remains unknown how apoptosis is relevant to the progression of the liver injury. This review summarizes the characteristics of both hepatic apoptosis and necrosis in pathogenesis of liver diseases. Apoptosis and necrosis represent alternative outcomes of different etiology during liver injury. Apoptosis is a main mode of cell death in chronic viral hepatitis, but is intermingled with necrosis in cholestatic livers. Necrosis is the principal type of liver cell killing in acetaminophen-induced hepatotoxicity. Anti-apoptosis as a strategy is beneficial to liver repair response. Therapeutic options of liver disease depend on the understanding toward pathogenic mechanisms of different etiology.     

Epithelial cell apoptosis and lung remodeling

Lung epithelium is the primary site of lung damage in various lung diseases. Epithelial cell apoptosis has been considered to be initial event in various lung diseases. Apoptosis signaling is classically composed of two principle pathways. One is a direct pathway from death receptor ligation to caspase cascade activation and cell death. The other pathway triggered by stresses such as drugs, radiation, infectious agents and reactive oxygen species is mediated by mitochondria. Endoplasmic reticulum has also been shown to be the organeile to mediate apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymai interaction plays important roles in these processes. Further understanding of apoptosis signaling and its regulation by novel strategies may lead to effective treatments against various lung diseases. We review the recent advances in the understanding of apoptosis signaling and discuss the involvement of apoptosis in lung remodeling. Cellular ＆ Molecular Immunology.     

肠道菌群和黏膜免疫与心血管疾病关系研究新进展

心血管病是目前导致死亡的主要原因之一。引起心血管疾病的主要发生机制是免疫性炎症。肠道菌群与黏膜免疫相互作用，同心血管系统生理功能维持和疾病发生关系密切。肠道菌群失调会导致血管炎、高血压和动脉粥样硬化的发生及心衰的加重。深入了解肠道菌群、黏膜免疫和心血管疾病之间的相互作用机制，可为心血管疾病防治开创新思路。     

Apoptosis: the sculptor of development

Apoptosis is a programmed mechanism of cell death recognized by its characteristic morphological and biochemical changes. Over the last decade, our understanding of the biochemistry of apoptosis has flourished. However, the physiological relevance of apoptosis remains elusive. Here, I propose that the process of programmed cell death plays an essential role in structural development. From pioneering studies almost a century ago to recent findings using modern technology, similar conclusions have emerged that highlight the fundamental role of apoptosis in vascular development. This review will recount these classic and modern studies as I survey evidence that implicates apoptosis in other aspects of development and ask how cell death can possibly contribute to homeostasis and development of the immune system. I briefly consider the mechanisms that may determine the fate of cells within the vasculature and propose new roles for the contribution of apoptosis to development and differentiation. More provocatively, I explore the possibilities that arise from this growing field of study, including prevention of developmental defects and even abnormal development after birth, such as neoplastic development. To realize these end points, the biochemical bases of apoptosis must be thoroughly understood.     

Induction of Apoptosis and p53 Expression in Immature Thymocytes by Direct Interaction with Thymic Epithelial Cells

Apoptosis of normal thymocytes was shown to be triggered by several mechanisms (e.g. glucocorticoids, γ-irradiation). In the present study the authors report on thymocyte apoptosis that is induced by thymic epithelial cells. The thymocytes undergo a massive apoptotic death within 24 h of cocultivation with thymic epithelial cell monolayers derived from primary cultures (PTEC) or from a thymic epithelial cell line (TEC). Non-thymic monolayers were inactive. Apoptosis induction in this experimental model requires direct contact between the thymocytes and the thymic epithelial monolayer and can be blocked by anti-CD2 and anti-LFA-1 antibodies. The immature CD3^−/+dull CD4⁺CD8⁺ thymocytes were the cells which undergo apoptosis. The fact that the authors are dealing with a massive apoptotic process of immature cells in the absence of exogenous antigen suggests that it involves the nonselected thymocytes. The apoptotic pathway selected by thymocytes following their culturing on TEC involves p53 expression. Indeed it was found that TEC-induced apoptosis, led to the accumulation of p53 protein that preceded the step of DNA fragmentation in freshly isolated thymocytes as well as in a glucocorticoid resistant thymoma cell line. Since glucocorticoid-induced thymocyte apoptosis is p53-independent, glucocorticoids are conceivably not involved in TEC-induced thymocyte death. The in vitro experimental model presented here may reflect the physiological sequence of events leading to thymocyte death in the thymus.     

Honorary membership of the European Histamine Research Society (EHRS)

The process of programmed cell death or apoptosis was already noted in 1842 by Vogt [1], but it was not until the more recent studies of Kerr et al. 1972 [2] that an explosion of interest in apoptosis research occurred. Genetic, biochemical and cellular analysis in certain mammals, in the nematode Caenorhabditis elegans and in the fruitfly Drosophila melanogaster have identified several apoptosis regulating genes. This indicates that programmed cell death is an active, genetically controlled process. Many of the known cell death regulators are homologous in mammals, nematodes and insects, indicating that apoptosis is an evolutionarily conserved process. Apoptosis can be induced via multiple independent signalling pathways which converge upon a common final effector machinery. This stimulates activation of latent cysteine proteases (caspases), which cleave vital cellular substrates and thereby lead to the death of cells. The regulatory pathways of apoptosis are becoming clear with the discovery of specific signalling molecules. It has become evident that many disease processes including autoimmunity and cancer can be caused by deregulation of the apoptotic process. With the discovery of novel cell surface-bound death receptors, their ligands and further insight into the apoptotic machinery within the cell, research may ultimately lead to the design of therapies that allow intervention in the apoptotic process. The aims of such strategies would be to turn on apoptosis in neoplastic cells or in lymphocytes that are causing autoimmune disease or to prevent cell death in degenerative disorders. This review describes current understanding of the molecular regulation of apoptosis, and focuses on issues relating to possible roles of defective cell death control in autoimmunity.     

Comparative gene identification-94--a pivotal regulator of apoptosis

Apoptosis is an active form of cell death that is carried out by proteins that are designed to kill the cell during normal mammalian development and tissue homeostasis. Cell death by apoptosis comprises a sequence of events leading to the activation of caspases which execute the fragmentation of the cellular protein and DNA leading to disintegration of the cell. This physiological neuronal apoptosis allows the nervous system to eliminate excess neurons. In addition, apoptotic cell death occurs in a variety of neuronal degeneration such as Alzheimer's disease. Here we describe second mitochondria-derived activator of caspases/Diablo as a new interacting protein of CGI-94 (comparative gene identification-94) which itself is probably involved in degenerative processes of Alzheimer's disease. Our findings that CGI-94 interacts with second mitochondria-derived activator of caspases/Diablo, inhibits nerve growth factor-induced neurite outgrowth and that its neuronal expression leads to cell death point to its pivotal role in the control of cellular survival. In conclusion, CGI-94 appears to be involved in processes of neuronal degeneration.     

On the mechanism of ionic regulation of apoptosis: would the Na+/K+-ATPase please stand up?

Apoptosis is an active process with distinct features including loss of cell volume, chromatin condensation, internucleosomal DNA fragmentation, and apoptotic body formation. Among the classical characteristics that define apoptosis, the loss of cell volume has become a very important component of the programmed cell death process. Changes in cell volume result from alterations in the homeostasis of ions and in particular the movement of Na+ and K+ ions. Most living cells have a high concentration of intracellular K+ and a low concentration of intracellular Na+. This is in contrast to the outside of the cell, where there is a high concentration of extracellular Na+ and a low concentration of extracellular K+. Thus a concentration gradient exists for the loss and gain of intracellular K+ and Na+, respectively. This gradient is maintained through the activity of various ionic channels and transporters, but predominantly the activity of the Na+/K+-ATPase. During apoptosis, there is compelling evidence indicating an early increase in intracellular Na+ followed by a decrease in both intracellular K+ and Na+ suggesting a regulatory role for these cations during both the initial signalling, and the execution phase of apoptosis. Recent studies have shown that the Na+/K+-ATPase is involved in controlling perturbations of Na+ and K+ homeostasis during apoptosis, and that anti-apoptotic Bcl-2 and Bcl-XL molecules influence these ionic fluxes. Finally, understanding the regulation or deregulation of ionic homeostasis during apoptosis is critical to facilitate the treatment of cardiovascular, neurological, and renal diseases where apoptosis is known to play a major role.     

Regulation and execution of apoptosis during Drosophila development.

The development of the Drosophila embryo into an adult fly is a process that integrates cell proliferation and differentiation with programmed cell death, or apoptosis. Apoptosis is an evolutionarily conserved process that is controlled in the developing fly by the products of the genes reaper, grim, and hid. We discuss the role of programmed cell death in the establishment and maintenance of correct patterning in the embryo, and examine the coordination of apoptosis with the hormonally controlled degeneration of larval tissues during metamorphosis. Finally, we address the architecture of the adult eye as an example of how programmed cell death plays a key role in the development of many adult structures.     

Links between apoptosis, proliferation and the cell cycle

Many physiological processes, including proper tissue development and homeostasis, require a balance between apoptosis and cell proliferation. All somatic cells proliferate via a mitotic process determined by progression through the cell cycle. Apoptosis (programmed cell death) occurs in a wide variety of physiological settings, where its role is to remove harmful, damaged or unwanted cells. Apoptosis and cell proliferation are linked by cell-cycle regulators and apoptotic stimuli that affect both processes. This review covers recent developments in the field and examines new evidence of the interconnection between apoptosis and cell proliferation.     

内质网应激与心血管疾病

内质网应激是细胞内一种适应性机制,持续或过强的内质网应激则诱导细胞凋亡,造成组织损伤.多项研究显示内质网应激是多种心血管疾病如动脉粥样硬化、缺血性心脏病、心肌肥大、心力衰竭及糖尿痛心肌病等发生、发展的共同通路,干预内质网应激可能成为心血管疾病治疗的新靶点.