Current Hypertension Reviews - Volume 7, Issue 4, 2011

Numerous humoral factors have been shown to be involved in regulating blood pressure and electrolyte-fluid balance in mammals, such as catecholamines, angiotensin peptides, aldosterone, natriuretic peptides, and endothelins. In 1993, a biologically active peptide discovered in human pheochromocytoma tissue by Kitamura and coworkers was added to the list. This peptide was termed adrenomedullin (AM) because it was abundantly present in adrenal medulla as well as in pheochromocytoma tissue. The action first characterized for AM was a potent blood pressure-lowering effect secondary to vasodilatation; however, 18 years have passed since the discovery, and AM is now known as a bioactive peptide with pleiotropic actions, including suppression of oxidative stress, angiogenesis, and neuroprotection, in various tissues and organs. It is widely recognized that humoral factors increasing blood pressure or fluid volume, such as angiotensin II and endothelins, exert undesirable effects exacerbating hypertensive organ damage, while those lowering them, such as natriuretic peptides, play protective roles in the cardiovascular system. Since the discovery of AM, many researchers have made substantial efforts to reveal the actions or roles of this bioactive peptide in the cardiovascular system. As a result, a large amount of scientific data has been accumulated, indicating a role of AM in the mechanism acting against elevation of blood pressure and progression of hypertensive organ damage. For example, experiments in vitro and in vivo have shown that AM has a protective role, probably as a local modulator in the cardiac ventricles by inhibiting hypertrophy or interstitial fibrosis of the myocardium. The active form of human AM consists of 52 amino acids with a ringed structure formed by a disulfide bond and an amidated carboxyl terminal, both of which are essential for biological activity. Based on homology in the amino acid sequence, AM is assumed to belong to the calcitonin gene-related peptide (CGRP) superfamily. The discovery of AM led to the identification of two bioactive peptides: proadrenomedullin N-terminal 20 peptide (PAMP), a blood pressure-lowering peptide, which was found to be processed from the AM precursor peptide preproAM; and adrenomedullin-2/intermedin, a member of the CGRP superfamily identified by two independent groups by searching genomes of humans and other vertebrates. This new peptide member has been shown to have biological actions, which are similar to those of AM. A number of basic and clinical studies have been carried out to verify the beneficial effects on hypertension or cardiovascular diseases associated with hypertension. Meanwhile, because AM levels in the blood of patients with hypertension or cardiovascular diseases are elevated in association with the severity of the illness, efforts have been made to explore the diagnostic values of measuring plasma AM levels in patients with those diseases. As discussed in this issue, it is now assumed that AM is beneficial as a therapeutic tool or as a diagnostic or prognostic marker for heart failure, acute myocardial infarction, or pulmonary hypertension. The receptors of AM or CGRP had been controversial, but the discovery of three subtypes of trans-membrane proteins of receptor activity-modifying proteins (RAMPs) revealed a unique receptor system: calcitonin receptor-like receptor (CLR) functions as a CGRP receptor or the AM type 1 or type 2 receptor depending on the subtype of RAMPs co-expressed. Experiments manipulating the genes of AM and these receptor components revealed not only the cardiovascular or neural protective actions of AM but also the indispensable role of AM and its signaling system in the process of embryogenesis. The detailed findings of these interesting studies are also described in this special issue. The aim of publishing this special issue is to provide current comprehensive knowledge on AM and related peptides. Each article was written by an expert in research on these bioactive peptides. The editor hopes that this special issue will help medical professionals in fields from basic research to clinical medicine understand the actions or role of AM in the cardiovascular and central nervous systems. It will also provide clear information about what is currently known and what remains to be clarified about AM for researchers working in a wide range of scientific fields. Finally, the editor would like to express sincere gratitude to all of the authors and reviewers for their thoughtful contributions to this special issue.

Adrenomedullin (AM), a hypotensive peptide, exerts powerful anti-oxidative, anti-inflammatory and antiatherosclerotic effects. In addition, AM strongly acts as an angiogenic and lymphangiogenic growth factor. Therefore, AM has attracted a great deal of attention as a potential therapeutic agent against cardiovascular diseases, such as acute myocardial infarction, heart failure, arteriosclerosis obliterans, pulmonary hypertension and secondary lymphedema. There are two receptor subtypes for AM, both of which are formed by the association of receptor activity-modifying proteins (RAMP2 or RAMP3), which are single transmembrane domain accessory proteins, with calcitonin receptor-like receptor (CLR), a G protein-coupled receptor. The CLR/RAMP2 and CLR/RAMP3 complexes form the AM1 and AM2 receptors, respectively. The specificity of AM for the AM1 receptor is higher than that for the AM2 receptor, which is conserved across multiple animal species. The AM1 receptor is essential for the development of the fetal cardiovascular system. Moreover, overexpression of the AM1 receptor in the vascular smooth muscle cell layers of the aorta can augment AM-induced blood pressure reduction and almost completely inhibit aortic vascular hypertrophy and inflammation caused by chronic angiotensin II infusion. Notably, the AM-AM1 receptor system was found to be crucially involved in both angiogenesis and lymphangiogenesis. In contrast, the cardiovascular functions of the AM2 receptor remain unclear, although there have been no reports showing differences in intracellular signaling via the two AM receptors. In this review, we focus on the molecular basis of AM1 receptor function and its roles in the cardiovascular system and also discuss the possibility of related drug discovery.

Adrenomedullin (AM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic vasoactive molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. To elucidate the in vivo roles of AM, we have established and analyzed genetically engineered AM mice and its receptor components. Heterozygotes of AM knockout mice (AM+/-) showed blood pressure elevation, severe cardiac hypertrophy, and fibrosis by pressure overload or angiotensin II infusion. On the other hand, vascular-specific AM-overexpressing mice were resistant to neointimal formation by arterial injury. Therefore, endogenous AM exerts protective effects against stress-induced cardiac hypertrophy, fibrosis, and arteriosclerosis, as well as a vasodilating effect. Homozygotes of AM knockout mice (AM-/-) were lethal at mid-gestation with abnormalities in vascular development. This finding first clarified the indispensable roles of AM in vascular development. We also showed that AM possesses novel angiogenic properties not only during development, but also in adults. Based on these observations, there is hope that AM can be used therapeutically. However, AM has a short half-life in the blood stream and its application in chronic disease has limitations. We generated knockout mice of receptor activitymodifying protein 2 (RAMP2), a small membrane protein that associates with the AM receptor. We found that the important vascular phenotypes of AM knockout mice were reproduced in RAMP2 knockout mice. This shows that RAMP2 is the key determinant of the vascular functions of AM. RAMP2 could be an attractive therapeutic target in cardiovascular diseases.

Adrenomedullin is a highly conserved peptide implicated in a variety of physiological processes ranging from pregnancy and embryonic development to tumor progression. This review highlights past and present studies that have contributed to our current appreciation of the important roles adrenomedullin plays in both normal and disease conditions. We provide a particular emphasis on the functions of adrenomedullin in vascular endothelial cells and how experimental approaches in genetic mouse models have helped to drive the field forward.

The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system and several functions have been suggested for brain AM. Until recently, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. The recent development of Cre/loxP conditional knockouts for this gene has opened a door for detailed physiopathological studies in the absence of neural AM. These animals present a subtle but very informative phenotype. For instance, it has been shown that neural stem cells lacking adm have delayed growth and their differentiation pattern is different from the one observed in wild type stem cells, producing less neurons and astrocytes but more oligodendrocytes. When the behavior of these animals was studied, it was found that knockout mice were more active, had less motor coordination and were more anxious than the control animals. As it relates to pain sensing, a very complex scenario has emerged; if pure spinal reflexes are tested, then AM functions as a pronociceptive modulator peptide. On the other hand, if the test involves encephalic processing, AM has the opposite effect and acts as an analgesic. Another field where the AM knockouts have shed additional light is in the involvement of AM in neuroprotection. Animals lacking neural AM had larger infarcts when subjected to focal brain ischemia and had compromised survival when exposed to hypobaria. These studies highlight the many functions of AM in the physiopathology of the nervous system.

We have studied the pleiotropic effects of adrenomedullin with knockout mice and found that it is a potent intrinsic antioxidant. Oxidative stress is related to cardiovascular as well as metabolic diseases. In this review, the coronary, pulmonary, and cerebrovascular damage that was observed in adrenomedullin-knockout mice is reviewed. An angiotensin II-loaded model, a hypoxia model, and a vascular occlusion model were applied to investigate vascular damage, and the results clarified the role of oxidative stress and the therapeutic potency of adrenomedullin in vascular protection. From in vivo and in vitro studies, adrenomedullin is known to antagonize oxidative stress by both inhibiting nicotinamide adenine dinucleotide phosphate oxidase and promoting the degradation of oxidative stress. In addition, the role of adrenomedullin in insulin resistance and obesity is discussed based upon the results of both clinical studies and basic research studies that used aged adrenomedullin-knockout mice. The pleiotropic effects of adrenomedullin suggest a number of new therapeutic targets in a variety of diseases.

Adrenomedullin (AM), a biologically active peptide first detected in human pheochromocytoma, has been shown to be present in various tissues or organs, such as blood vessels, cardiac muscle, kidneys, and adipose tissue. AM exerts a wide range of actions, including those lessening cardiovascular damage associated with hypertension or obesityrelated disorders. This bioactive peptide was found to circulate in the human blood, and its plasma levels in hypertensive or obese patients were increased when compared with control subjects. Experiments with animal models of hypertension revealed a possible protective role of AM acting against elevation of blood pressure or hypertensive end-organ damage. In normotensive subjects, a rise in the plasma AM level was associated with future elevation of blood pressure. According to our recent study examining local residents, significant correlations were noted between plasma AM levels and body mass index, serum triglycerides, insulin, or high density lipoprotein cholesterol levels. Expression of AM in adipose tissue of an animal model of obesity was found to be higher than that of the control, and AM was produced and secreted from cultured adipocytes, where the AM receptor components were expressed. Animal experiments showed improved insulin resistance following AM infusion. Collectively, these findings suggest protective roles of AM acting against the progression of hypertensive organ damage and obesity-related metabolic disorders.

Adrenomedullin (AM) is a unique bioactive molecule, originally isolated from human pheochromocytoma by monitoring cyclic adenosine monophosphate (cAMP) elevation in platelets. PreproAM mRNA and its translated peptide have been recognized to be widely distributed in the organs of rodents and humans, including heart and vasculature. AM exhibits vasorelaxant activity working on vascular endothelial cells and smooth muscle cells. In addition, AM modulates left ventricular contractility and remodeling in the hypertrophied/failing heart, and alters the structural integrity of the vascular wall. Furthermore, immunocompetent cells, such as macrophage-, and mast cell-derived AM might contribute to the pathogenesis of cardiovascular disorders. Most biological actions mediate cAMP-protein kinase A signaling, whereas cAMP-independent pathways, such as the nitric oxide/soluble guanylate cyclase/cGMP pathway, modulated in molecules/signaling associated with anti-oxidative stress and anti-apoptotic pathways, are also reported. Overall, the actions of AM are assumed to be beneficial against vasoconstrictive factors activated in the diseased heart and vascular wall, whereas some reports imply that the biological activity of AM might be dependent on circumstances. Specifically, inotrophic action, activation of adhesion molecules and smooth muscle proliferation by AM has been debated. In this review, we will present the recent advances in AM research, and discuss the controversy of AM actions in cardiac and vascular tissues.

Many neurohumoral factors play an important role in regulation of the cardiovascular system and in the pathophysiology of heart failure. Adrenomedullin (AM) is a potent long-lasting vasodilatory peptide that was discovered in acid extracts of human pheochromocytoma tissues. Both AM and its gene expression are widely distributed in the cardiovascular system, including the heart, vessels, and kidneys. AM co-localizes with its receptor components such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the heart, vessels and kidneys, suggesting that it plays an important role in the regulation of cardiovascular function through an autocrine and/or paracrine mechanism. AM has inotropic action in vitro and in vivo and inhibits cardiac hypertrophy in myocytes as well as proliferation and collagen production in cardiac fibroblasts. These results suggest that AM functions as an antifibrotic, antihypertrophic and positive inotropic factor in the failing heart. In addition, AM has anti-apoptotic, angiogenic, anti-inflammatory and anti-oxidant effects. Several mechanisms such as cAMP/PKA, NO/cGMP, PI-3K/Akt and/or ERK are thought to mediate cellular AM signaling, suggesting that increased AM levels play a protective role in heart failure. Indeed, acute AM administration exerts beneficial vasodilatory, diuretic, natriuretic and inotropic effects on experimental and human heart failure. A recent pilot study has shown that AM has potential as a therapeutic drug in the clinical setting of acute decompensated heart failure.

Cardiovascular disease is a leading cause of death and disability and despite advances in treatment there remains an ongoing need to develop new therapeutic interventions. Accumulating evidence points towards an important role for the adrenomedullin (AM) family of peptides in pressure/volume homeostasis and indicate potential as therapeutic agents in a variety of clinical settings including cardiovascular disease. Plasma levels of AM are raised in cardiovascular disease in proportion to severity of cardiac dysfunction and are useful prognostic indicators of outcome. AM administration in both experimental and human heart failure induces a beneficial spectrum of biological action including reduced arterial and atrial pressures, improved cardiac output, inhibition of plasma aldosterone and preservation or augmentation of urinary sodium excretion. Experimental data also supports a role for AM in cardioprotection in cardiac ischemia/reperfusion injury and in the progression of heart failure following myocardial infarction. Thus, strategies to manipulate the AM system may prove beneficial as adjunctive therapy in cardiovascular disease.