Serotonin associated injury and survival signalling in myocardium: Receptor dependant and non receptor targets for cytoprotection
Introduction
Basic research during the last decade has highlighted a number of intracellular signalling pathways that regulate the rate at which cardiac cells undergo irreversible injury and their potential for therapeutic manipulation to limit cell death, especially during reperfusion. Although several important therapeutic drugs act on platelet-derived serotonin in acute coronary syndromes, the direct effects of serotonin on the ischaemic myocardium are not well understood. The limited evidence available so far strongly suggests that receptor-dependent and non-receptor pathways activated by serotonin may influence the myocardial response to ischaemia-reperfusion. Targeting these pathways could have therapeutic potential in acute myocardial infarction and will afford fundamental insights into the mechanisms of ischaemia-reperfusion injury. Our preliminary data show that serotonin exerts concentration-dependent effects on myocardium during ischaemia-reperfusion, enhancing tissue survival at low concentrations and exacerbating necrosis at high concentrations. We hypothesise that the protective effects of serotonin are mediated by 5HT1B and/or 5HT2B receptors, coupling through one or more of the survival cassettes PI3K/Akt, ERK1/2 and NO/cGMP/PKG. We propose that the deleterious effects of serotonin are mediated through a non-receptor mechanism, namely mitochondrial H2O2 generation by MAO-A. We will adopt a comprehensive pharmacological and biochemical approach in a rat model of acute myocardial infarction to interrogate these mechanisms of serotonin action. The studies will provide fundamental information on serotonin's pathophysiological roles which we believe may be therapeutically tractable in the quest for effective infarct-limiting interventions.
Aims of Project
- The primary aim of this project is to define the effects and mechanisms of action of serotonin (5-hydroxytryptamine; 5-HT) on the myocardium during ischaemia and reperfusion.
- The specific experimental objectives are:
- to obtain a detailed characterisation of serotonin's concentration- and time-dependent effects on myocardial susceptibility to ischaemia-reperfusion injury
- to investigate the roles of 5HT1B and 5HT2B receptor activation in the pro-survival action of serotonin
- to investigate the roles of the NO/cGMP, PI3K/Akt and ERK1/2 signalling pathways in the pro-survival action of serotonin
- to explore the contribution of MAO-A-derived H2O2 in the pro-injury actions of serotonin.
Funder
British Heart Foundation
Project Value
£141,823
Duration
three years
