Role of apoptosis in remodeling after myocardial infarction

It has been suggested that apoptosis may be responsible for a significant amount of cardiomyocyte death during acute myocardial infraction as well as for a progressive loss of surviving cells in failing hearts. Typical apoptosis can indeed be induced in cardiomyocytes at the experimental conditions. In actual heart diseases, in contrast, there is very little direct morphological evidence of apoptosis in cardiomyocytes occuring at any stage of myocardial infarction and heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. For that reason, the potential efficacy of therapeutic intervention to prevent apoptosis remains controversial. This review will survey available data from both animals and humans to critically assess the role of cardiomyocyte apoptosis during myocardial infarction and its relevance to myocardial remodeling and during progression to heart failure. Also considered will be nonmyocyte interstitial cells, which have received less attention than myocytes despite definitive evidence of their apoptosis in the infarcted heart and recent studies suggesting that blockade of apoptosis among these cells mitigates postinfarction cardiac remodeling and heart failure. We conclude from our survey that there are many hurdles to surmount before regulation of apoptosis can be clinically applied in the treatment of myocardial infarction and heart failure.

Morphological aspects of apoptosis in heart diseases.

Background: Diabetes mellitus is associated with cognitive deficits in humans and animals. These deficits are paralleled by neurophysiological and structural changes in brain. In diabetic animals, impairments of spatial learning, memory, and cognition occur in association with distinct changes in hippocampus, a key brain area for many forms of learning and memory and are particularly sensitive to changes in glucose homeostasis. However, the multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood. Apoptosis plays a crucial role in diabetes-induce neuronal loss in hippocampus. Methods: The effects of diabetes on hippocampus and cognitive/behavioral dysfunctions in experimental models of diabetes are reviewed, with a focus on the negative impact on increased neuronal apoptosis and related cellular and molecular mechanisms. Results: Of all articles that were assessed, most of the experimental studies clearly showed that diabetes causes neuronal apoptosis in hippocampus through multiple mechanisms, including oxidative stress, inhibition of caspases, disturbance in expression of apoptosis regulator genes, as well as deficits in mitochondrial function. The balance between pro-apoptotic and anti-apoptotic signaling may determine the neuronal apoptotic outcome in vitro and in vivo models of experimental diabetes. Conclusions: Dissecting out the mechanisms responsible for diabetes-related changes in the hippocampal cell apoptosis helps improve treatment of impaired cognitive and memory functions in diabetic individuals.

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The Effect of Diabetes Mellitus on Apoptosis in Hippocampus: Cellular and Molecular Aspects.

Previously, we reported that cloned embryos derived from an immortalized bovine mammary epithelial cell line (MECL) failed to develop beyond 12- to 16-cell stage. To analyze whether induction of a senescent-like phenotype in MECL can improve their ability to support the development after transfer into enucleated oocytes, we treated MECL with DNA methylation inhibitor 5-aza-2-deoxycytidine (Aza-C), histone deacetylase inhibitors trichostatin A (TSA), sodium butyrate (NaBu), or 5-bromodeoxyuridine and used those cells for nuclear transfer. Primary bovine fetal fibroblasts (BFF) were used as control. All agents were capable to induce features of senescence including reduced cell proliferation, enlarged cell size with a considerable proportion of cells stained positive for acidic senescence-associated b-galactosidase and G1/S cell cycle boundary arrest in MECL. Aza-C treatment induced genome demethylation. Acetylation of H3 and H4 was increased after TSA treatment in both MECL and BFF, whereas no obvious changes in global H3 or H4 acetylation were detected after NaBu treatment. Nuclear transfer experiments following diverse treatments demonstrated that the induced senescent-like phenotype of MECL did not confer their ability to support embryonic development, although 7.3% of reconstructed embryos derived from NaBu-treated cells developed to morula stage. Intriguingly, a much higher proportion of cloned embryos developed to blastocysts when using NaButreated BFF, compared with using untreated BFF (59% versus 26%). Our results suggest that the developmental failure of donor nuclei from bovine immortal cells could not be reversed by induction of senescent-like phenotype. The beneficial effect of NaBu on the developmental potential of cloned embryos reconstructed from BFF merits further studies. apoptosis, early development, embryo, mammary glands, oocyte development

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Induction of a Senescent-Like Phenotype Does Not Confer the Ability of Bovine Immortal Cells to Support the Development of Nuclear Transfer Embryos

Methylmercury (MeHg) can cause deleterious effects in vertebrate tissues, particularly in the central nervous system. MeHg interacts with sulfhydryl groups from low and high molecular weight thiols in the blood, which can facilitate MeHg uptake into different tissues. The purpose of this study was to examine the effect of MeHg-Cysteine (MeHg-Cys) complex administration on Hg-uptake in cerebral areas (cortex and cerebellum), liver and kidney of adult mice. Animals were divided into four groups: control (1 mL/kg distilled water), MeHg (2 mg/kg), Cys (2 mg/kg) and MeHg-Cys complex (0.8 molar ratio). Mice received one intraperitoneal injection per day for 60 consecutive days. Treatment with MeHg significantly increased mercury concentrations in all tissues analysed when compared with the control group. The accumulation of mercury in brain and in liver was further increased in animals that received MeHg-Cys complex when compared with the MeHg alone group. However, renal Hg decreased in MeHg-Cys treated mice, when compared with the group treated only with MeHg. In summary, the transport of MeHg-Cys complex was tissue-specific, and we observed an increase in its uptake by liver and brain as well as a decrease in kidney.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-7843.2010.00577.x

Complex Methylmercury–Cysteine Alters Mercury Accumulation in Different Tissues of Mice

Apoptosis (Programmed Cell Death) is a genetically regulated, morphologically distinct form of cell death that can be initiated by many different physiological and pathological stimuli. Such strategic intracellular programming is initiated in many instances during normal life cycle and development in order to maintain the homeostasis of a multicellular organism, to eliminate unwanted cells. However, apoptosis is also involved in a wide range of pathologic conditions, including neurodegenerative and cardiovascular diseases, cancer and autoimmune diseases. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Here we review the basic components of the death machinery, discuss their interaction in regulation of apoptosis, and describe the main pathways that are used to activate apoptosis.

N V Marozkina

Papers

Molecular mechanisms of apoptosis.