Adrenomedullin: regulator of systemic and cardiac homeostasis in acute myocardial infarction

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Abstract

During and following acute myocardial infarction, a variety of endogenous mediators are elevated, one of which is adrenomedullin (AM). AM is a multifunctional peptide that has been identified as having a putative beneficial role following an ischemic insult at both systemic and local levels. Classically described as a potent vasodilator, natriuretic, and diuretic agent, experimental infarct models also demonstrate AM to exhibit antiproliferative and antiapoptotic functions in the myocardium, counterregulating the effects of mediators such as angiotensin-II and endothelin-1. Less well documented are the angiogenic and inflammatory modulating potentials of AM, which may also contribute toward reducing adverse ventricular remodeling. The review examines clinical and experimental studies, looking at the effects of AM and cellular mechanisms that could be involved in mediating cardioprotective effects and ultimately optimizing left ventricular remodeling. Finally, the possibility of enhancing endogenous actions of AM by pharmacological intervention is considered.

Introduction

Since the discovery of adrenomedullin (AM) a little over a decade ago (Kitamura et al., 1993), potential roles of this peptide in various aspects of cardiovascular regulation have been examined. Although originally isolated from human pheochromocytoma, AM is widely expressed and exerts a multitude of actions, predominantly although not exclusively, in the cardiovascular system. The myocardium and vascular endothelium are recognized as the principal sites of expression (Eto et al., 2003). Clinical and experimental studies of AM have shown that the peptide has marked influences on pressure and volume homeostasis, which come into play during many pathophysiological conditions. However, there is abundant evidence that AM plays important roles in regulating local tissue responses to several physiological and pathological factors, including hypoxia, mechanical loading, inflammation, and pressor mediators such as aldosterone, endothelin-1 (ET-1), and angiotensin-II (AT-II; Eto et al., 2003). This review focuses on the systemic and local autocrine/paracrine actions of AM in the ischemic myocardium where local expression of the peptide is markedly up-regulated. AM may act in several ways, influencing the acute and long-term outcomes of an acute ischemic episode through cytoprotective actions and through actions regulating systemic hemodynamics, neurohormonal responses, inflammatory mediators, oxidative stress, and cellular proliferation and growth.

Section snippets

Sources of the adrenomedullin family of peptides

Human mature AM is a 52-amino acid peptide containing a 6-amino acid ring and a C-terminal amidation sequence, which are highly conserved, sharing moderate sequence homology to the calcitonin family of regulatory peptides (calcitonin, CGRP-α and -β, and amylin; Champion et al., 1999). The porcine sequence is similar to that of human AM with a single substitution (Kitamura et al., 1994), whereas in the rat and mouse the sequence contains 50 amino acids (Sakata et al., 1993).

The human AM gene is

Calcitonin receptor-like receptors/receptor activity modifying proteins

Presently, the prevailing notion is that AM specifically mediates it action through complexes composed of calcitonin receptor-like receptor (CL) combined with receptor activity modifying proteins (RAMP) as well as CGRP receptors. The CL/RAMP2 and RAMP3 complexes are called AM receptors. CL/RAMP2 (AM1) and CL/RAMP3 (AM2) complexes have higher AM specificity than CGRP, which has high selectivity for the CL/RAMP1 (Poyner, 1997). Both CL and RAMP are independent proteins with differing tissue

Overview of cardiovascular adrenomedullin physiology

Characteristic descriptions of AM-mediated cardiovascular and renal actions include reduced systemic vascular resistance, diuresis, natriuresis, and increased cardiac output.

Adrenomedullin release in plasma and urine

Total, mature, and glycated AM plasma and urine concentrations in patients admitted within 24 hr of the onset of acute MI symptoms peak within the acute phase of injury correlating with changes in plasma BNP levels, a natriuretic peptide established as a marker for volume overload in the LV (Nagaya et al., 1999). Urinary AM excretion also follows a similar trend to plasma AM concentration and is correlated to levels of excreted sodium. Because the levels of urinary AM are several times higher

Coronary vasodilator actions of adrenomedullin

The ability of AM to induce vasodilation of both peripheral and coronary circulation increases the cardiac efficiency. With reduced peripheral vascular resistance, the ability of blood to enter and leave the heart is markedly improved in a situation where there is an increase in the sympathetic tone or circulating pressor mediators such as AT-II and ET-1. During infarction, the coronary microcirculation is further compromised by greater ventricular wall stress, coronary vasoconstriction, and

Adrenomedullin and reperfusion injury

In isolated rat heart preparations, AM given prior to reperfusion is found to reduce infarct size, whereas administration prior to ischemia has less effect. The cardioprotection at reperfusion was blocked by coinfusion with l-NAME (Hamid & Baxter, 2004). In AM pretreated rats, reduced infarct size was correlated to enhanced nitrotyrosine immunoreactivity in the endothelium of coronary blood vessels and leukocytes indicating peroxynitrite-mediated cardioprotection (Looi, 2003). Also, AM

Adrenomedullin and inflammatory mediators

The inflammatory process is essential for initiating the repair of the injured myocardium through scar formation, but the complex cascade of events occurring as a result of the interaction of a multitude of inflammatory cells and cytokines can also be an important determinant of altered cardiac function and inappropriate ventricular remodeling (Frangogiannis et al., 2002). At present, the approach of studying AM in regulating the inflammatory process in MI has not been documented. However, the

Adrenomedullin and its influence on angiogenesis

Collateral vessel formation has long been recognized as a feature of ischemic disease (Helisch & Schaper, 2003). The mechanisms by which new capillary formation (angiogenesis) occurs are still not completely understood. Hemodynamic factors appear to be of paramount importance, but both hypoxia and inflammation stimulate the expression and release of trophic factors, including cytokines and growth factors such as fibroblast growth factor, platelet-derived growth factor, VEGF and angiopoetin-1

Ventricular remodeling

Tissue remodeling occurring following damage to the myocardium is a complex interplay among hemodynamic, neurohormonal, and inflammatory factors (Fig. 3). A progressive phenotypic change caused by direct and indirect actions of systemic and local pressor mediators cause myocyte hypertrophy, interstitial fibroblast proliferation, and excess matrix secretion in the noninfarct region. This hypertrophic and fibroproliferative response ultimately leads to a less compliant ventricular chamber and

Therapeutic possibilities for adrenomedullin augmentation

To date, no long-term clinical studies have been carried out to assess the possibilities of AM-enhancing agents as therapies in ischemic heart disease. Experimental evidence highlights that AM has the potential to influence the pathological process in both the acute phase of MI and the subsequent remodeling and hemodynamic features associated with chronic heart failure. Thus far, exploration of potential clinical benefits of AM is limited.

Conclusion and perspective

Increasing evidence points toward AM functioning as a peptide that counterregulates activities of pressor agents also released during MI. It is likely that autocrine/paracrine actions of AM in the myocardium signals buffer against hypertensive, proliferative, oxidant, and apoptosis signals induced by AT-II, ET-1, and aldosterone. Preliminary studies in noncardiac tissue suggest that AM not only is an angiogenic agent in its own right but also is able to modulate the inflammatory response. The

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