Targeting p38-MAPK in the ischaemic heart: kill or cure?

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The p38-MAPK pathway plays an important role in myocardial ischaemia/reperfusion injury and has been implicated in the regulation of cardiac gene expression, myocyte hypertrophy, inflammation, energetic metabolism, contractility, proliferation and apoptosis. The activation of p38-MAPK by dual phosphorylation during myocardial ischaemia aggravates lethal injury. However, under other circumstances activation can protect the heart, and recent evidence suggests that the mechanism of p38-MAPK activation may differ by circumstance. Determining the precise mechanism of activation during myocardial ischaemia is of considerable importance, since it may allow prevention of the detrimental, but not the beneficial, activation of p38-MAPK and lead to the identification of the relevant signalling molecules to be targeted for pharmaceutical intervention.

Introduction

Ischaemic heart disease is a major cause of morbidity and mortality, accounting for 20% of all deaths in the UK [1]. Although effective interventional therapies have been devised to treat acute coronary syndromes, atherosclerotic plaques within coronary arteries still cause rapid occlusion, myocardial infarction (MI) and death [2]. MI generally results from plaque rupture/erosion with secondary thrombus formation in a coronary artery, culminating in an acute reduction of blood supply to the myocardium and is characterised by the rapid development of myocardial necrosis [3]. MI affects cardiac performance through loss of functional myocardium and total occlusion of the vessel for as little as 20–30 min can result in irreversible myocardial injury. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed ‘reperfusion injury’. Ischaemia/reperfusion injury may lead to further myocardial infarction, cardiac arrhythmias and contractile dysfunction [4]. The resultant myocardial fragility can result in left ventricular (LV) remodelling [5]. This is characterised by thinning of the infarcted myocardium, LV chamber dilation, fibrosis and hypertrophy of viable myocytes [6]. Early remodelling may be adaptive and maintain LV function, but long-term remodelling may contribute to functional breakdown and eventually pump failure [7]. Understanding the intracellular processes leading to cell death following ischaemia and unravelling the cellular and molecular mechanisms that trigger LV remodelling following MI is an invaluable approach in the development of therapies to prevent the progression of heart failure.

Section snippets

p38-MAPK

p38-Mitogen-activated protein kinase (p38-MAPK) has emerged as an important mediator of ischaemic injury, as well as a variety of other biological processes including inflammation, cell growth, cell differentiation, cell cycle and cell death in many tissue types [8]. In the heart, the p38-MAPK pathway has been implicated in the regulation of cardiac gene expression, myocyte hypertrophy, inflammation, energetic metabolism, contractility, proliferation and apoptosis [9, 10, 11, 12, 13, 14]. It

Activation of p38-MAPK

p38-MAPK is composed of two domains: a 135-residue N-terminal domain composed largely of β-sheets and a 225-residue C-terminal domain being largely helical and containing the catalytic site, magnesium binding sites, and phosphorylation lip [17]. The catalytic (ATP binding) site lies at the junction between the two domains [19], and the common docking domain is located towards the C-terminus and is involved in the specific binding of upstream activators, substrates and phosphatases to p38-MAPK [

p38-MAPK in the heart: kill or cure?

Many reports demonstrate that during myocardial ischaemia p38-MAPK activation enhances lethal injury [32, 33, 34] and inhibition protects against it [32, 35, 36, 37, 38]. However, there is also evidence to suggest that p38-MAPK activation confers protection to the heart [39, 40, 41, 42, 43, 44], much of which is from investigators studying the phenomenon of ischaemic preconditioning (IPC). IPC, a powerful adaptive mechanism, was initially described in 1996 as a mechanism whereby a short

References and recommended readings

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