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Cardiomyocyte death and the ageing and failing heart
David F Goldspink1, Jatin G Burniston, Lip-Bun Tan
1The Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, 15-21 Webster Street, UK. d.goldspink@livjm.ac.uk
Insights
Catecholamines induce both apoptosis and necrosis in rat heart cells in vivo, with necrosis occurring more frequently. This suggests catecholamines may contribute to heart failure progression due to sympathetic over-activation.
Area of Science:
- Cardiovascular biology
- Cell death mechanisms
- Myocardial pathophysiology
Background:
- Mammalian cardiomyocytes possess limited regenerative capacity, leading to contractile element loss and reduced cardiac function during aging and heart failure.
- Apoptosis and necrosis are key cell death phenotypes, but in vitro findings may not accurately reflect in vivo events.
- Further in vivo studies are crucial to understand cardiomyocyte death pathways and their role in heart failure.
Purpose of the Study:
- To investigate the in vivo induction of cardiomyocyte apoptosis and necrosis by catecholamines.
- To quantify the relative incidence of apoptosis versus necrosis induced by catecholamines.
- To explore the potential etiological role of catecholamines in heart failure progression.
Main Methods:
- Immunohistochemical analysis using anti-caspase 3 and anti-myosin antibodies to identify apoptosis and necrosis, respectively.
- In vivo administration of natural or synthetic catecholamines in a rat model.
- Optimization of hormone dose, temporal, and spatial parameters for damage assessment.
- Assessment of myocyte damage in both cardiac and soleus muscles.
Main Results:
- A single catecholamine injection induced both cardiomyocyte apoptosis and necrosis in vivo.
- Necrosis occurred 4-10 times more frequently than apoptosis.
- Significant myocyte damage, including apoptosis and necrosis, was observed in the soleus muscle.
- High co-localization of apoptosis and necrosis in myocytes suggested secondary necrosis.
Conclusions:
- Catecholamines can induce both apoptosis and necrosis in cardiomyocytes in vivo, with necrosis being predominant.
- The findings suggest a potential etiological role for catecholamines in heart failure progression.
- Sustained high levels of catecholamines, resulting from sympathetic over-activation, may contribute to myocyte loss and cardiac dysfunction.
Abstract:
Mammalian cardiomyocytes have limited regenerative capacity, such that cell death can result in a net loss of viable contractile elements and a decrease in cardiac functional reserve, both during normal ageing and after insults to the myocardium leading to heart failure. At least four types of cell death have been described, with apoptosis and necrosis being the most extreme phenotypes and most extensively studied. Many of the classical morphological and biochemical features associated with these forms of cell death have been derived from studies conducted in vitro and these may not always faithfully reflect events occurring in vivo. Before therapeutic interventions can be realistically developed, more studies need to be undertaken in vivo to simultaneously investigate these different death pathways, their control mechanisms and their relative contributions in depleting the pool of viable cardiomyocytes. We recently demonstrated immunohistochemically that a single injection of either a natural or synthetic catecholamine induces both cardiomyocyte apoptosis (identified by an anti-caspase 3 antibody) and necrosis (identified by an anti-myosin antibody) in the rat heart in vivo. After optimising the experimental conditions for hormone dose and temporal and spatial peaks of damage, the incidence of necrosis was 4-10 times greater than the incidence of apoptosis. Myocytes in the soleus muscle were also severely (7-10 %) damaged, involving both apoptosis and necrosis. In both striated muscles high levels of myocyte co-localisation for apoptosis and necrosis were observed, suggesting that secondary necrosis had occurred in most of the apoptotic myocytes in vivo. The ability of the catecholamines to cause myocyte death suggests that they might play an aetiological role in the progression of heart failure where over-activation of the sympathetic system results in sustained pathophysiological levels of these catecholamines.