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Regulation of cardiac myocyte cell death
Angela Clerk1, Sharon M Cole, Timothy E Cullingford
1NHLI Division (Cardiac Medicine Section), Faculty of Medicine, Imperial College of Science, Technology and Medicine, Flower's Building, Armstrong Road, South Kensington, London SW7 2AZ, UK. a.clerk@imperial.ac.uk
Abstract:
Cardiac myocyte death, whether through necrotic or apoptotic mechanisms, is a contributing factor to many cardiac pathologies. Although necrosis and apoptosis are the widely accepted forms of cell death, they may utilize the same cell death machinery. The environment within the cell probably dictates the final outcome, producing a spectrum of response between the two extremes. This review examines the probable mechanisms involved in myocyte death. Caspases, the generally accepted executioners of apoptosis, are significant in executing cardiac myocyte death, but other proteases (e.g., calpains, cathepsins) also promote cell death, and these are discussed. The two principal cell death pathways (death receptor- and mitochondrial-mediated) are described in relation to the emerging structural information for the principal proteins, and they are discussed relative to current understanding of myocyte cell death mechanisms. Whereas the mitochondrial pathway is probably a significant factor in myocyte death in both acute and chronic phases of myocardial diseases, the death receptor pathway may prove significant in the longer term. The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway. These proteins are described and their possible functions are discussed. The commitment to cell death is also influenced by protein kinase cascades that are activated in the cell. Whereas certain pathways are cytoprotective (e.g., phosphatidylinositol 3'-kinase), the roles of other kinases are less clear. Since myocyte death is implicated in a number of cardiac pathologies, attenuation of the death pathways may prove important in ameliorating such disease states, and possible therapeutic strategies are explored.
Insights
Cardiac myocyte death involves necrosis and apoptosis, utilizing shared machinery. Understanding these cell death pathways and proteases is key to developing therapies for heart disease.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiac myocyte death contributes to various heart pathologies.
- Necrosis and apoptosis, though distinct, may share cell death mechanisms.
- The cellular environment influences the cell death outcome, creating a spectrum of responses.
Purpose of the Study:
- To review the probable mechanisms involved in cardiac myocyte death.
- To discuss the roles of caspases, other proteases, and cell death pathways in myocyte demise.
- To explore potential therapeutic strategies for ameliorating cardiac pathologies by targeting cell death pathways.
Main Methods:
- Review of existing literature on cardiac myocyte death mechanisms.
- Discussion of caspases, calpains, cathepsins, and Bcl-2 family proteins.
- Analysis of death receptor and mitochondrial-mediated cell death pathways.
Main Results:
- Caspases are crucial for apoptosis, while other proteases like calpains and cathepsins also contribute to myocyte death.
- The mitochondrial pathway is significant in both acute and chronic myocardial diseases.
- The death receptor pathway may become more relevant in the long term.
- Bcl-2 family proteins regulate the mitochondrial pathway, and protein kinase cascades influence commitment to cell death.
Conclusions:
- Cardiac myocyte death pathways are complex, involving multiple proteases and signaling cascades.
- Targeting these pathways offers potential therapeutic strategies for cardiac diseases.
- Further research into the specific roles of different pathways and proteins is warranted.