Current Protein and Peptide Science - Volume 14, Issue 4, 2013

Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action but is now known to exert a wide range of physiological effects, including cardiovascular protection, neovascularization, and apoptosis suppression. A variety of tissues, including the gastrointestinal tract, have been shown to constitutively produce AM. Pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1, and lipopolysaccharides, induce the production and secretion of AM. Conversely, AM induces the downregulation of inflammatory cytokines in cultured cells. Furthermore, AM downregulates inflammatory processes in a variety of different colitis models, including acetic acid-induced colitis and dextran sulfate sodium-induced colitis. AM exerts antiinflammatory and antibacterial effects and stimulates mucosal regeneration for the maintenance of the colonic epithelial barrier. Here, we describe the first use of AM to treat patients with refractory ulcerative colitis. The results strongly suggest that AM has potential as a new therapeutic agent for the treatment of refractory ulcerative colitis.

Many neurohumoral factors play important roles in the regulation of the cardiovascular system and in the pathophysiology of cardiovascular disease. Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue but now known to exert a variety of effects within the cardiovascular system. AM expression is widely distributed throughout the cardiovascular system and has been identified in the heart, lungs, blood vessels and kidneys. In addition, the co-localization of AM and its receptor components suggest AM acts as an autocrine and/or paracrine factor to play a key role in the regulation of cardiovascular function. Evidence also strongly suggests that cardiovascular disease is associated with elevated levels of AM in plasma and tissue. In this review, we describe the pathophysiological changes in plasma and local AM associated with myocardial infarction, heart failure and pulmonary hypertension. We also describe the clinical application of AM in cardiovascular disease from the viewpoints of diagnosis and treatment.

Sensory nerves are abundant in lymphoid organs and rapidly release the neuropeptide calcitonin gene-related peptide (CGRP) in response to injury or infection. CGRP directly acts on macrophages and dendritic cells and inhibits the capacity of these cells to produce inflammatory cytokines and to present antigens to T cells. Effector mechanisms, by which CGRP acts on innate immune cells, include upregulation of IL-10, IL-10-independent induction of the inducible cAMP early repressor (ICER) and inhibition of NF-κB activity. Engagement of the CGRP receptor, which is composed of receptor activity modifying protein-1 (RAMP1) and calcitonin receptor-like receptor (CLR), increases cellular cAMP levels leading to the activation of protein kinase A (PKA). PKA appears crucial for mediating the antiinflammatory effects of CGRP. Available evidence therefore indicates that CGRP acts as a negative regulator of innate immune responses and contributes to limiting tissue damage in inflammatory disorders. In sepsis caused by mixed-bacterial infection, however, antiinflammatory activities of CGRP may exaggerate leading to immunosuppression and impaired host defense.

Insulin resistance is defined as a preliminary step of type 2 diabetes mellitus with decreased insulin action evoked by continuous postprandial hyperglycemia, which is provoked by high fat and calories dieting, a lack of physical activity and obesity. In the early phase of type 2 diabetes mellitus, patients have a hyperinsulinemia to compensate deficient insulin action by increased secretion from the pancreas to maintain euglycemia. Then, pancreatic β cells progressively decrease secretion function, resulting in the development of diabetes mellitus with decreased serum insulin levels. Accumulating evidences show that insulin resistance is associated with hypertension. However, the mechanisms underlying hypertension associated with type 2 diabetes mellitus have still unknown. Therefore, to elucidate the mechanisms of insulin resistance-induced hypertension, we investigated that the effects of hyperinsulinemia or hyperglycemia on vascular responses mediated by perivascular nerves including sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves). In this article, we show evidence that insulin resistance-induced hypertension could be resulted from increased density and function of sympathetic nerve, and decreased density and function of CGRPergic nerves. Furthermore, our findings provide a new insight into the research of therapeutic drugs for insulin resistance- induced hypertension.

Vertebrates have expanded their habitats from aquatic to terrestrial environments, which has accompanied the evolution of cardiovascular and osmoregulatory hormones. Specifically, mammals have developed mechanisms to maintain high blood pressure and blood volume, while extant fishes have developed hypotensive and Na-extruding mechanisms to adapt to the marine environment where they underwent a vast diversification. The CGRP family is one of the hormone systems that decrease blood pressure and blood volume. Within the CGRP family of teleost fishes, we found that adrenomedullins (AMs) have diversified and five paralogs (AM1-5) form an independent subfamily. Based on this discovery in fishes, we found AM2 and AM5 in mammals. In mammalian species that have AM2 and/or AM5, the peptides assume greater importance in the case of pathophysiological disturbances in pressure and fluid balance such as hypertension and cardiac and renal failure. In addition, novel functions of AM peptides have been suggested by the discovery of AM2 and AM5 in mammals. Current research on the CGRP family is focused on the identification of new receptors for AM2/AM5 and the establishment of AM2 knockout mice, which will enable new developments in the basic and clinical research on this intriguing hormone family. Importantly, comparative fish studies can contribute to new developments in our understanding of the function of the AM peptides.

Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin (AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast to AM and CGRP, IMD binds non-selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature, heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression, underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD protects the mammalian vasculature, myocardium and kidney from acute ischaemia-reperfusion injury, chronic oxidative stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure.

Islet amyloid polypeptide (IAPP, amylin) is a 37 amino acid residue hormone expressed mainly by pancreatic islet beta cells and to less extent by some gastrointestinal endocrine cells and by certain regions in central nervous system. In experimental systems a number of different effects have been ascribed to IAPP but the in vivo importance of many of them is still unknown. At least effects on the central nervous system and on endocrine pancreatic cells are likely to be physiologically relevant. In these tissues calcitonin receptors and receptor activity-modifying proteins (RAMPs) 1 and 3, creating high affinity IAPP receptors have been identified. How expression of the components of these complexes are regulated and how further signaling is conducted are more or less unknown. IAPP is most well-known for its ability to aggregate into amyloid fibrils in islets of Langerhans in association with type 2 diabetes leading to loss of beta cells. In addition, amyloid is deposited between endocrine cells and between such cells and capillaries and most likely disturbs important interactions between the cells. How IAPP receptor complexes are affected by the amyloid formation process or by amyloid itself, or vice versa, are completely unknown.

Amylin (islet amyloid polypeptide) and amyloid beta protein (Aβ), identified as proteinaceous deposits within the pancreas of diabetics and the brain of Alzheimer’s patients respectively, share many biophysical, physiological and neurotoxic properties. Although no specific “Aβ receptor” has been identified, emerging evidence suggests that the amylin receptor serves a putative target receptor for the actions of Aβ; in the brain. The amylin receptor consists of a calcitonin receptor dimerized with receptor activity-modifying proteins and is widely distributed within central nervous system. Aβ can directly activate this G protein-coupled receptor and trigger multiple intracellular signal transduction messengers and pathways that include calcium, cAMP, ERK1/2 and Fos. Growing evidence suggests that amylin and amylin receptors are involved in many aspects of neurodegenerative pathophysiology. Developing therapeutic strategies aimed at modulating amylin receptor function may prove useful for treatment of neurodegenerative diseases such as Alzheimer’s disease.