Multiple roles of adrenomedullin revealed by animal models

Caron, Kathleen M.; Smithies, Oliver

doi:10.1002/jemt.10046

Cited by 12 publications

(16 citation statements)

References 45 publications

(49 reference statements)

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“…In this study, we find that adrenomedullin peptide, secreted from the epicardium, is a potent regulator of cardiomyocyte proliferation during embryogenesis. Since the discovery of adrenomedullin (protein ¼ AM, gene ¼ Adm) in 1993 (Kitamura et al, 1993), many diverse biological functions have been described for this small circulating peptide during development, normal physiology and disease (Caron and Smithies, 2002;Karpinich et al, 2011). We, and others, have previously shown that genetic deletion of the highly conserved Adm gene in mice causes embryonic lethality at mid-gestation (Caron and Smithies, 2001;Shindo et al, 2001;Shimosawa et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Epicardial‐derived adrenomedullin drives cardiac hyperplasia during embryogenesis

Wetzel-Strong

Klein

et al. 2013

Developmental Dynamics

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Background Growth promoting signals from the epicardium are essential for driving myocardial proliferation during embryogenesis. In adults, these signals become reactivated following injury and promote angiogenesis and myocardial repair. Therefore, identification of such paracrine factors could lead to novel therapeutic strategies. The multi-functional peptide adrenomedullin (Adm = gene, AM = protein) is required for normal heart development. Moreover, elevated plasma AM following myocardial infarction offers beneficial cardioprotection and serves as a powerful diagnostic and prognostic indication of disease severity. Results Here, we developed a new model of Adm overexpression by stabilizing the Adm mRNA through gene-targeted replacement of the endogenous 3′ untranslated region. As expected, Admhi/hi mice express three-times more AM than controls in multiple tissues, including the heart. Despite normal blood pressures, Admhi/hi mice unexpectedly showed significantly enlarged hearts due to increased cardiac hyperplasia during development. The targeting vector was designed to allow for reversion to wild-type levels by means of Cre-mediated modification. Using this approach, we demonstrate that AM derived from the epicardium, but not the myocardium or cardiac fibroblast, is responsible for driving cardiomyocyte hyperplasia. Conclusions AM is produced by the epicardium and drives myocyte proliferation during development, thus representing a novel and clinically relevant factor potentially related to mechanisms of cardiac repair after injury.

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Section: Introductionmentioning

confidence: 99%

Epicardial‐derived adrenomedullin drives cardiac hyperplasia during embryogenesis

Wetzel-Strong

Klein

et al. 2013

Developmental Dynamics

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“…Among its many functions ADM has been shown to play a key role in mammalian development, as ADM knockout in mice is embryonically lethal (Garayoa et al, 2002; Ando and Fujita, 2003). Expression studies have, however, shown that ADM is initially limited to discrete embryonic regions, whereas at later stages of development it is nearly ubiquitously expressed (Montuenga et al, 1997, 1998; Caron and Smithies, 2002). While its exact mechanism(s) of action during development are not fully characterized, its expression coincides with the onset of both differentiation, for example during bone formation, and several chemotactic cell processes, including neural crest cell migration (Montuenga et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin is expressed during rodent dental tissue development and promotes cell growth and mineralization

Musson

McLachlan

Sloan

et al. 2010

Biology of the Cell

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Background information. ADM (adrenomedullin) has pleiotropic effects, including regulation of inflammation, infection, angiogenesis, mineralized‐tissue formation and development. Recently, we demonstrated up‐regulation of the ADM transcript in diseased pulpal tissue while the protein is sequestered within the dentine extracellular matrix during dentinogenesis. The present study aimed to characterize ADM localization during rodent dental tissue development and determine its potential effects on dental cells. Finally, we sought to profile ADM transcript levels in adult organs and tissues to compare its expression in teeth relative to other tissues. Results. Immunohistochemical analysis of developmental rat oral tissues indicated that, at E16 (embryonic day 16), ADM was present in dental epithelium and, by E18, ADM localized to the dental papilla and inner and outer dental epithelia. By E20, ADM was detected in secretory odontoblasts and ameloblasts and exhibited a similar expression profile to that of the key dentinogenesis signalling molecule, TGF‐β1 (transforming growth factor‐β1). Cell growth analysis in the dental MDPC‐23, OD‐21 and control 3T3 cell lines exposed to ADM (range 10−15–10−7 M) together with EDTA‐extracted DMPs (dentine matrix proteins) (range 0.00001–1000 mg/ml) containing comparable concentrations of ADM demonstrated that ADM stimulated a biphasic response in dental cell growth, comparable with that of DMPs, with peak stimulation observed at ∼10−11 M. For mineralization analysis, cell lines were exposed to combinations of 50 μg/ml ascorbic acid, 10 mM β‐G (β‐glycerophosphate), 10−8 M DEX (dexamethasone) and ADM (range 10−15–10−7 M). The results demonstrated that ADM could substitute for DEX to stimulate mineralization. Postnatally, multiple tissue expression profiling indicated abundant ADM levels in tongue and pulpal tissues. Conclusions. During oral and dental tissue development ADM initially localizes to epithelial tissue, whereas during later stages it is present in mineralized secreting cells, including odontoblasts. ADM may regulate proliferation and mineralization processes during development, whereas, in adulthood, it may be important for maintaining dental tissue homoeostasis.

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“…growth. [5][6][7] Depending on the particular cell type, AM may promote or inhibit cell growth. 8,9 Although AM is expressed in normal prostate epithelium and prostate cancer, its function in the prostate remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…AM appears to be ubiquitously expressed 2,5 and can perform a variety of functions, including vasodilatation, bronchodilation, hormone secretion control, renal homeostasis and regulation of cell growth. [5][6][7] Some cell types are stimulated to proliferate by AM, 7,8 whereas other cell types are growth-inhibited. 9 The calcitonin receptor-like receptor (CRLR), in conjunction with receptor activity-modifying protein-2 (RAMP-2) and -3 (RAMP-3), functions as AM receptors in numerous cell types.…”

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confidence: 99%

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

Gonzalez-Moreno

Calvo

Joshi

et al. 2004

Intl Journal of Cancer

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Human adrenomedullin (AM) is a 52 amino acid peptide, which shares homology with the calcitonin gene-related peptide. Overexpression of AM in the prostate carcinoma cell line PC-3 results in growth inhibition with a 20% (for human AM) and 35% (for rat AM) increase in doubling time compared to parental or mocktransfected cells. We demonstrate by gene expression profiling that AM overexpression results in the dysregulation of approximately 100 genes. Examples of such genes include many involved in the formation of the cytoskeleton, cell adhesion and the extracellular matrix, as well as regulators of the cell cycle and apoptosis, cytokines and transcription factors. Several genes related to cell growth arrest, such as GADD45, IGF-BP6 and RUNX-3, are upregulated by AM. Interestingly, interleukin-13 receptor ␣2 (IL-13R␣2) transcripts were significantly increased in clones overexpressing AM, which was confirmed by semiquantitative RT-PCR analysis. In addition, PC-3 cells treated with AM showed an overexpression of IL-13R␣2, which was abolished when cells were preincubated with an anti-AM blocking antibody. When PC-3 cells overexpressing AM and the IL-13R␣2 were treated with the highly specific IL13-PE38 cytotoxin, which binds to this receptor, a concentration-dependent inhibition of protein synthesis was observed. The IC 50 (concentration of cytotoxin inhibiting protein synthesis by 50%) ranged from 1 to 4 ng/ml. This cytotoxicity was specific as it was neutralized by the excess of IL-13 and confirmed by clonogenic assays. This study describes a novel AM-induced mechanism of tumor sensitization through the upregulation of functional IL-13R␣2 chain, an ideal target for the highly specific recombinant chimeric cytotoxin IL13-PE38. © 2004 Wiley-Liss, Inc.Key words: cDNA microarrays; prostate cancer; adrenomedullin; IL-13R␣2; gene expression profiling Prostate carcinoma is the second leading cause of cancer mortality among men in the United States. 1 The 5-year relative survival rate for the patients whose tumors are diagnosed with local or regional disease approaches 100%, but the relative 10-and 15-year survival rates are reduced to 75% and 54%, respectively. 1 Although localized prostate cancer may be successfully treated, 70% of patients eventually progress and develop metastasis. The current nonsurgical therapeutic regimens for treating prostate carcinoma include radio-, hormonal-and chemotherapy, as well as a combination of these regimens, depending on specific circumstances of the patient. The limited success of treating particular forms of prostate cancer requires that additional targets for therapy be identified and tested.Expression of adrenomedullin, an amidated peptide that was originally isolated from human pheochromocytoma, 2 has been documented in both the human and rat prostate, 3 human prostate carcinoma 4 and prostate cancer cell lines, 4 where it has been suggested that adrenomedullin (AM) may act as an autocrine/ paracrine factor. Human AM consists of 52 amino acids (50 amino acids for rat AM) and shar...

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Multiple roles of adrenomedullin revealed by animal models

Cited by 12 publications

References 45 publications

Epicardial‐derived adrenomedullin drives cardiac hyperplasia during embryogenesis

Epicardial‐derived adrenomedullin drives cardiac hyperplasia during embryogenesis

Adrenomedullin is expressed during rodent dental tissue development and promotes cell growth and mineralization

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

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