Adrenomedullin

Adrenomedullin, a 52 amino acid peptide, is a member of the calcitonin peptide family Ref-1 and is widely expressed in many tissues and organs. It has been shown to have a variety of physiological functions, including immune-modulating, direct bactericidal, diuretic and potent vasodilatory activity Ref-1-5, and in healthy conditions, circulates at low picomolar concentrations Ref-6. It can act as both a hormone and a cytokine (often termed a “hormokine” Ref-7) in an autocrine and paracrine manner Ref-8. Its potent vasodilatory and hypotensive response is elicited through an initial increase in cyclic adenosine monophosphate levels, and a subsequent production of nitric oxide Ref-1, 9-10.

Adrenomedullin plays a significant role in the regulation of many cytokines and mediators, and is a key mediator in maintaining vascular tone and a constant blood supply to individual organs and tissues. This makes adrenomedullin crucial in homeostasis and in many disease conditions. The importance of adrenomedullin is illustrated by its central role in the up- and down-regulation of cytokines and other mediators, as well as its own stimulatory and inhibitory Ref-11-12 effect on cytokine production. Indeed, Interleukin (IL)-1β and tumour necrosis factor (TNF) are two of the most potent stimulators for adrenomedullin production Ref-13 and adrenomedullin itself is up-regulated by hypoxia, bacterial products and shear stress Ref-7.

 

Cytokine regulation by Adrenomedullin

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References Adrenomedullin

Ref-1: Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. Apr 30 1993;192(2):553-560.

Ref-2: Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. Apr 2000;21(2):138-167.

Ref-3: Linscheid P, Seboek D, Zulewski H, Keller U, Muller B. Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology. Jun 2005;146(6):2699-2708.

Ref-4: Nishikimi T. Adrenomedullin in the kidney-renal physiological and pathophysiological roles. Curr Med Chem. 2007;14(15):1689-1699.

Ref-5: Pio R, Martinez A, Unsworth EJ, et al. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem. Apr 13 2001;276(15):12292-12300.

Ref-6: Lim SC, Morgenthaler NG, Subramaniam T, Wu YS, Goh SK, Sum CF. The relationship between adrenomedullin, metabolic factors, and vascular function in individuals with type 2 diabetes. Diabetes Care. Jun 2007;30(6):1513-1519.

Ref-7: Schuetz P, Marlowe RJ, Mueller B. The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review. Clin Chem Lab Med. Sep 25 2014.

Ref-8: Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech. Apr 15 2002;57(2):120-129.

Ref-9: Shimekake Y, Nagata K, Ohta S, et al. Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells. J Biol Chem. Mar 3 1995;270(9):4412-4417.

Ref-10: Eto T. A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. Peptides. Nov 2001;22(11):1693-1711.

Ref-11: Kubo A, Minamino N, Isumi Y, et al. Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J Biol Chem. Jul 3 1998;273(27):16730-16738.

Ref-12: Wong LY, Cheung BM, Li YY, Tang F. Adrenomedullin is both proinflammatory and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line. Endocrinology. Mar 2005;146(3):1321-1327.

Ref-13: Sugo S, Minamino N, Shoji H, et al. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. Feb 6 1995;207(1):25-32.

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