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Apoptosis--new opportunities for novel therapeutics for heart diseases
1Cardiovascular Sciences, DuPont Pharmaceuticals Company, Wilmington, DE 19880-0400, USA.
Insights
Cardiomyocyte apoptosis, a programmed cell death, occurs in heart diseases. Understanding its molecular pathways offers new therapeutic targets for heart failure and myocardial infarction.
Area of Science:
- Cardiology
- Cell Biology
- Molecular Medicine
Background:
- Apoptosis is a programmed cell death process with distinct molecular and genetic underpinnings.
- Evidence indicates cardiomyocyte apoptosis contributes to various cardiac pathologies, including heart failure and myocardial infarction.
Purpose of the Study:
- To review the molecular mechanisms and signaling pathways involved in cardiomyocyte apoptosis.
- To highlight the therapeutic potential of targeting these pathways for cardiac disease treatment.
Main Methods:
- Review of scientific literature on cardiomyocyte apoptosis.
- Analysis of signaling pathways including tyrosine kinase receptors, G-protein coupled receptors, and NF-κB.
- Identification of stimuli triggering apoptosis, such as oxidative stress and cardiotoxins.
Main Results:
- Cardiomyocyte apoptosis is implicated in ischemic and non-ischemic heart failure, myocardial infarction, and arrhythmias.
- Key signaling pathways involved include TRK-induced SAPK/MARK and ceramide signaling, GPCR signaling, and NF-κB activation.
- Stimuli like oxygen radicals, cytokines, neurohormones, and cardiotoxic drugs induce apoptosis.
Conclusions:
- Cardiomyocyte apoptosis plays a significant role in cardiac remodeling and dysfunction.
- Targeting molecular pathways of apoptosis presents novel therapeutic opportunities for heart failure, arrhythmias, and myocardial infarction.
Abstract:
Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (e.g., TNFalpha, FAS) neurohormonal factors (angiotension II), cardiotoxic drugs (e.g., doxorubicin) and mechanical, stretch situations. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis. Most prominent are: 1) Tyrosine kinase receptors (TRK) induced signaling involving stress or mitogen activated protein kinases (SAPK/MARK) and sphingolipids metabolites (ceramide); 2) G-protein coupled receptor (GPCR) signaling (Galphai, Galphaq) and 3) NF(K) B activation. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of diverse molecular targets associated with cardiomyocyte apoptosis provide new opportunities for pharmacologic manipulation, that may lead to discovery and development of therapeutic strategies for treatment of heart failure, arrhythmias and myocardial infarction.