Disease relevance of ADM

• Only VEGF and ADM were constitutively secreted, and hypoxia further stimulated the release of these vasodilator peptides [1].
• Pertussis toxin, an activator of the G-protein, Gi, inhibited ADM-stimulated cGMP accumulation, whereas cholera toxin, a stimulator of the Gs G-protein and subsequently cAMP accumulation, had little effect [2].
• Because CRLR determines the binding specificity of ADM, the CRLR gene is thought to be a susceptibility gene of hypertension [3].
• ADM is also implicated in hemodynamic abnormalities during liver cirrhosis, but whether ADM is increased late after liver transplantation is unknown [4].
• RESULTS: Treatment with 100 ng/ml progesterone increased VEGF-A, VEGF-B and ADM contents in cultured leiomyoma cells and normal myometrial cells [5].

Psychiatry related information on ADM

• Recently, elevated plasma levels of ADM were found in patients with schizophrenia, bipolar affective disorder and autism, suggesting the involvement of ADM in the pathophysiology of mental diseases [6].
• We propose there is a potential role for microbial products in enhancing mucosal defense mechanisms and that adrenomedullin participates in the prevention of local infection, thus contributing to host defense mechanisms [7].
• The relaxant effect of adrenomedullin might lead to novel clinical applications for erectile dysfunction [8].
• Adrenomedullin and nitrite levels in children with primary nocturnal enuresis [9].

High impact information on ADM

• This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM) [10].
• In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting adrenomedullin and of the mechanisms regulating gene expression [11].
• In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed [11].
• In Section IV the various actions of adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered [11].
• The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin [12].

Chemical compound and disease context of ADM

• CONCLUSIONS: These results suggest that CDB-2914 down-regulates VEGF, ADM and their receptor contents and modulates PR isoform contents in cultured leiomyoma cells in a cell-type-specific manner [5].
• These findings, coupled with the demonstration that ADM exerts an aldosterone antisecretagogue action and a proliferogenic effect on cultured aldosteronoma cells, make it likely that endogenous ADM system plays a potentially important role in the paracrine or autocrine functional control of Conn's adenomas [13].
• Hypoxic Induction of Receptor Activity-Modifying Protein 2 Alters Regulation of Pulmonary Endothelin-1 by Adrenomedullin: Induction under Normoxia Versus Inhibition under Hypoxia [14].
• Inhibition of human [125I]calcitonin gene-related peptide-I ([125I]hCGRP-I) binding by human adrenomedullin (hADM), its N-terminal truncated fragments, CGRP and amylin, and cyclic AMP accumulation were examined in the human neuroblastoma cell line SK-N-MC [15].
• Effects of levonorgestrel-releasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis [16].

Biological context of ADM

• Here we report for the first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis [17].
• ADM was also correlated with increased diastolic (r = 0.68, P < 0.04) and systolic (r = 0.66, P < 0.05) blood pressure in late Htx [18].
• In view of ADM's biological properties, these results might suggest a compensatory role for ADM against further development of vasoconstriction and fluid retention states after heart transplantation [18].
• ADM stimulates both JAr and HTR-8/SV neo cell proliferation [19].
• 1. Adrenomedullin (ADM), a recently discovered circulating hypotensive peptide, shares limited sequence homology with the sensory nerve-derived vasodilator, calcitonin gene-related peptide (CGRP) [20].

Anatomical context of ADM

• In concordance, increased messenger RNA (mRNA) levels of VEGF and ADM were found at culturing macrophages in hypoxia [1].
• In human trigeminal ganglia, mRNA for ADM and the two CGRP1 receptors was systematically present [21].
• Adipocyte transcriptional activity, glycerol release, and insulin-mediated glucose transport were studied after exogenous CGRP and ADM exposure [22].
• In summary, CGRP and ADM are two differentially regulated novel adipose tissue secretion factors exerting autocrine/paracrine roles [22].
• Depletion of calcium stores in the endoplasmic reticulum (ER) with 1 microM cyclopiazonic acid or 150 nM thapsigargin, or inhibition of ryanodine-sensitive receptors in the ER with 10 microM ryanodine attenuated the ADM-induced NO release [23].

Associations of ADM with chemical compounds

• These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies [17].
• Further, the ability of CGRP and ADM to activate adenylate cyclase in cerebromicrovascular and astroglial cell cultures was determined, and the receptors involved were characterized pharmacologically [21].
• We used a nitrite assay to demonstrate that ADM (10 pM to 100 nM) stimulated NO release from the cells, with a maximal response observed with 1 nM at 30 min [23].
• No relationship was observed between ADM and left ventricular mass index, aldosterone and creatinine [18].
• NO responses to ADM were mimicked by 1 mM dibutyryl cAMP, a cAMP analog, and were abrogated by 5 microM H-89, a protein kinase A inhibitor [23].

Physical interactions of ADM

• The seven amino acids of human RAMP2 (86) and RAMP3 (59) are critical for agonist binding to human adrenomedullin receptors [24].
• Coupling of hADM binding to cAMP stimulation is less efficient than for hCGRP-I and is reduced by deletion of the unique 12 amino acid sequence of hADM N-terminal to the ring structure [15].
• Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners [25].

Regulatory relationships of ADM

• Small hairpin RNA silencing of ADMR in pancreatic cancer cells blocked adrenomedullin-induced growth and invasion, indicating that this receptor is involved in the autocrine actions of adrenomedullin [26].
• Though the PCR data demonstrated the presence of mRNA for both CGRP1 and adrenomedullin receptors the rank order of potency (CGRP>adrenomedullin>amylin) for the blood flow increase indicated vasodilatation for these peptides was induced by activation of CGRP1 receptors [27].
• Furthermore, upregulation of the ADM gene induced by DHT was inhibited by co-administration with a VEGF-neutralizing antibody [28].
• EGF significantly stimulated ADM production in normal trophoblasts but did not in PE placentas [29].
• Adrenomedullin regulates cellular glutathione content via modulation of gamma-glutamate-cysteine ligase catalytic subunit expression [30].

Other interactions of ADM

• These data indicate that adrenomedullin acting via ADMR increases the aggressiveness of pancreatic cancer cells and suggests that these molecules may be useful therapeutic targets [26].
• We also found that adrenomedullin increased cAMP levels in HeLa EBNA and 293 EBNA cells, expressing both the receptor activity-modifying protein 2 and calcitonin receptor-like receptor proteins [31].
• Cells co-expressing the CL receptor and RAMP3, produced such a response, as in mammals, indicating that the human ADM molecule is not the cause of the previous unresponsiveness [32].
• Novel calcitonin-(8-32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins [33].
• RAMP2 and adrenomedullin mRNAs were increased after 4h, but no change was observed for RAMP1 [34].

Analytical, diagnostic and therapeutic context of ADM

• METHODS AND RESULTS: Stimulation of HSCs with ADM resulted in a dose-dependent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca2+]i and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method [35].
• Specific mRNA for ADM (RT-PCR and Northern blot) was detected in HSCs and increased after incubation of cells with cytokines [35].
• METHODS: Circulating ADM and its relationship with parameters of cardiovascular hemodynamics, humoral factors and renal function were determined in normal subjects and Htx early (1, 2, 4, 8, 15 and 30 days) and late (32 +/- 16 months) after transplantation [18].
• Such an increase likely results from renal impairment associated with volume regulation abnormalities, suggesting a potential role for ADM in volume regulation after liver transplantation [4].
• OBJECTIVES: Circulating adrenomedullin (ADM), a potent vasorelaxing and natriuretic peptide involved in cardiovascular homeostasis, is increased after cardiac and renal transplantation [4].

References