Disease relevance of Adm

• Identification of adrenomedullin receptors in cultured rat astrocytes and in neuroblastboma x glioma hybrid cells (NG108-15) [1].
• The elevated expression of adrenomedullin which occurs postnatally in the TGF-beta1 null mouse may be a cause or a consequence of the multifocal wasting syndrome which is characteristic of postnatal TGF-beta1 null mice [2].
• These data suggest that genetically determined absence of Adm may be one cause of nonimmune hydrops fetalis in humans [3].
• We find that Adm(-/-) embryos die at midgestation with extreme hydrops fetalis and cardiovascular abnormalities, including overdeveloped ventricular trabeculae and underdeveloped arterial walls [3].
• Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes [4].

High impact information on Adm

• Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice [5].
• Adrenomedullin, a recently identified potent vasodilator, is expressed widely and has been suggested to have functions ranging from reproduction to blood pressure regulation [3].
• Urocortin and adrenomedullin prevent lethal endotoxemia by down-regulating the inflammatory response [6].
• Selective inactivation of adrenomedullin over calcitonin gene-related peptide receptor function by the deletion of amino acids 14-20 of the mouse calcitonin-like receptor [7].
• Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo [8].

Chemical compound and disease context of Adm

• Exposure of cultured adult rat ventricular cardiac myocytes to hypoxia (1% O2) resulted in a significant, time-dependent increase in adrenomedullin mRNA levels [4].
• Accelerated cardiac hypertrophy and renal damage induced by angiotensin II in adrenomedullin knockout mice [9].
• Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in rats [10].
• We have examined the effects of adrenomedullin (AM), a novel hypotensive peptide first isolated from human pheochromocytoma, on receptor binding and cyclic AMP (cAMP) generation in primary cultures of mouse astrocytes [11].
• The angiogenic peptide adrenomedullin (ADM) has been implicated as a mediator of the increased risk of endometrial hyperplasia and cancer resulting from the use of tamoxifen for the treatment and prevention of breast cancer [12].

Biological context of Adm

• CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors [13].
• Here we have characterized ADM binding sites in cultured rat astrocytes using human [125I]ADM(1-52) as radioligand [1].
• Using restriction fragment length variants on a DNA panel of interspecific backcross mice, we mapped Adm to a distal region of mouse chromosome 7 [14].
• Transfection studies revealed that the 5'-flanking sequence of adrenomedullin was capable of mediating a hypoxia-inducible increase in transcription [4].
• Two potential hypoxia-inducible factor-1 (HIF-1) consensus binding sites were identified in the mouse adrenomedullin promoter at -1095 and -770 nucleotides from the transcription start site [4].

Anatomical context of Adm

• Adrenomedullin upregulates M2-muscarinic receptors in cardiomyocytes from P19 cell line [15].
• We previously reported that adrenomedullin (AM), a vasodilating hormone secreted from blood vessels, promotes proliferation and migration of human umbilical vein endothelial cells (HUVECs) [16].
• In conclusion, we have identified novel ADM receptors coupled to cAMP formation in cultured rat astrocytes and NG108-15 cells [1].
• ADM is predominantly synthesized in the adrenal medulla, but immunoreactive ADM has also been detected in the human brain [1].
• In addition, when cultured mouse embryo fibroblasts were treated with a neutralizing monoclonal antibody against TGF-beta1, the levels of adrenomedullin expression were statistically reduced compared to untreated cells [2].

Associations of Adm with chemical compounds

• Angiotensin II-induced insulin resistance is enhanced in adrenomedullin-deficient mice [17].
• Forskolin, captopril, or TGF-beta had no effect on the transcription or synthesis of ADM in mesangial cells [18].
• Human adrenomedullin (AM) and human calcitonin gene-related peptide (CGRP) produced a concentration-dependent relaxation in mouse aorta, precontracted with noradrenaline [19].
• LU208075 treatment normalized the upregulated expression of ET-1 and adrenomedullin, as well as the deficit in MIFI, but did not affect the increased ETRA and ETRB expression or the elevated plasma glucose levels found in nontreated animals [20].
• Retinas were removed and either fixed in formalin for confocal microscope evaluation of retinal vascular filling or transferred to RNALater for quantitative reverse transcriptase-polymerase chain reaction to evaluate expression of NOS-3, NOS-1, ET-1, ETRA, ETRB, and the angiogenic factor adrenomedullin [20].

Regulatory relationships of Adm

• The calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS blocks CGRP and adrenomedullin vasoactive responses in the microvasculature [21].
• In conclusion, endogenous adrenomedullin in the brain may inhibit sympathetic activation through its antioxidant action [22].
• Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells [23].
• Adrenomedullin suppresses interleukin-1beta-induced tumor necrosis factor-alpha production in Swiss 3T3 cells [24].

Other interactions of Adm

• These results indicated (1) that a pure population of osteoclast-like cells can be prepared by LCM and gene expression of this population can be analyzed by RT-PCR and (2) that RT-PCR shows that osteoclast-like cells express RAMP2, CTR and CRLR, suggesting the potential for adrenomedullin binding to osteoclast-like cells [25].
• Amylin and adrenomedullin: novel regulators of bone growth [26].
• Bile duct ligation induced a significant increase in mRNA levels of the cannabinoid receptor (CB)-1, adrenomedullin and NOS-2 in the liver of NOS-3 KO and WT mice [27].
• Thus, we examined whether adrenomedullin, an antioxidant peptide, is involved in the central regulation of arterial pressure through sympatho-modulatory action [22].
• These defects include thinning of the aorta and carotid arteries and are very similar to those of the recently characterized adrenomedullin (AM) gene KO despite the presence of elevated immunoreactive AM in PAM KO embryos [28].

Analytical, diagnostic and therapeutic context of Adm

• These observations were confirmed by quantitative real time RT-PCR for adrenomedullin in both embryos and postnatal animals, as well as in cultured mouse embryo fibroblasts from TGF-beta1 null and wildtype mice [2].
• Adrenomedullin in cell culture supernatant was measured by a radio-immunoassay (with a detection level of 3.2 pmol/l) [18].
• Chromatin immunoprecipitation assays indicated that the estrogen receptor binds directly to the ADM promoter region and RAMP3 intron after estrogen administration [29].
• Acetylcholine (ACh)- and adrenomedullin-induced endothelium-dependent vasorelaxation of renal vessels significantly improved in ghrelin-pretreated mice (%Delta renal perfusion pressure by 10(-7) M ACh -63.5 +/- 3.7 versus -41.2 +/- 5.5%; P < 0.05) [30].
• Multiple roles of adrenomedullin revealed by animal models [31].

References