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Ider M, Naseri A, Ok M, Erturk A, Durgut MK, Iyigun SS. Surveilling brain damage using brain biomarkers in hypoglycemic neonatal calves with diarrhea. Front Vet Sci 2023; 10:1240846. [PMID: 38026658 PMCID: PMC10644661 DOI: 10.3389/fvets.2023.1240846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Hypoglycemia is a condition associated with neonatal diarrhea in calves, leading to increased mortality and neurological clinical signs. The aim of the present study was to determine the development of brain damage in hypoglycemic calves with neonatal diarrhea and the diagnostic and prognostic significance of these biomarkers. Ten healthy and 50 hypoglycemic calves with diarrhea were included in the study. Clinical examination, blood gases and complete blood count were performed at admission. Blood serum calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolysis isoenzyme-1 (UCHL-1), activitin A (ACT), adrenomodullin (AM) concentrations, and creatine kinase-BB (CK-BB) enzyme activity were measured using commercial bovine-specific ELISA kits to assess brain damage. Of the hypoglycemic calves enrolled in the study, 13 (26%) survived and 37 (74%) died. In addition, 32 (64%) of the calves had severe acidosis and 24 (48%) had sepsis. S100B, GFAP, UCHL-1, CK-BB (p < 0.001) and NSE (p < 0.05) concentrations were significantly higher in hypoglycemic calves compared to healthy calves, while ACT concentrations were lower. Blood glucose concentration was negatively correlated with serum S100B, GFAP, UCHL-1, and CK-BB enzyme activity and positively correlated with ACT in hypoglycemic calves (p < 0.01). Brain injury biomarkers were not predictive of mortality (p > 0.05). Morever, severe hypoglycemia, severe acidosis and sepsis variables were not found to have sufficient capacity to predict mortality when considered alone or together (p > 0.05). In conclusion, brain damage may develop as a consequence of hypoglycemia in calves. S100B, NSE, GFAP, UCHL-1, ACT, and CK-BB concentrations can be used to diagnose brain damage in hypoglycemic calves. However, the variables of severe hypoglycemia, severe acidosis, and sepsis together with the biomarkers of brain injury have a limited value in predicting the prognosis of neonatal calves with diarrhea.
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Affiliation(s)
- Merve Ider
- Faculty of Veterinary Medicine, Department of Internal Medicine, Selcuk University, Konya, Türkiye
| | - Amir Naseri
- Faculty of Veterinary Medicine, Department of Internal Medicine, Selcuk University, Konya, Türkiye
| | - Mahmut Ok
- Faculty of Veterinary Medicine, Department of Internal Medicine, Selcuk University, Konya, Türkiye
| | - Alper Erturk
- Faculty of Veterinary Medicine, Department of Internal Medicine, Hatay Mustafa Kemal University, Hatay, Türkiye
| | - Murat Kaan Durgut
- Faculty of Veterinary Medicine, Department of Internal Medicine, Selcuk University, Konya, Türkiye
| | - Suleyman Serhat Iyigun
- Faculty of Veterinary Medicine, Department of Internal Medicine, Selcuk University, Konya, Türkiye
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Martínez-Herrero S, Martínez A. Adrenomedullin: Not Just Another Gastrointestinal Peptide. Biomolecules 2022; 12:biom12020156. [PMID: 35204657 PMCID: PMC8961556 DOI: 10.3390/biom12020156] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 12/11/2022] Open
Abstract
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as GI hormones, regulating numerous physiological processes such as gastric emptying, gastric acid release, insulin secretion, bowel movements, or intestinal barrier function. Furthermore, it has been recently demonstrated that AM/PAMP have an impact on gut microbiome composition, inhibiting the growth of bacteria related with disease and increasing the number of beneficial bacteria such as Lactobacillus or Bifidobacterium. Due to their wide functions in the GI tract, AM and PAMP are involved in several digestive pathologies such as peptic ulcer, diabetes, colon cancer, or inflammatory bowel disease (IBD). AM is a key protective factor in IBD onset and development, as it regulates cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function and mucosal epithelial repair, and promotes a beneficial gut microbiome composition. AM and PAMP are relevant GI hormones that can be targeted to develop novel therapeutic agents for IBD, other GI disorders, or microbiome-related pathologies.
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Imai A, Toriyama Y, Iesato Y, Hirabayashi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Liu T, Xian X, Zhai L, Dai K, Tanimura K, Liu T, Cui N, Yamauchi A, Murata T, Shindo T. Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:999-1015. [PMID: 28322199 DOI: 10.1016/j.ajpath.2017.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/19/2017] [Indexed: 11/29/2022]
Abstract
Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.
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Affiliation(s)
- Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yuichi Toriyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yasuhiro Iesato
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Kun Dai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Keiya Tanimura
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Teng Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | | | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
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Martínez-Herrero S, Martínez A. Adrenomedullin regulates intestinal physiology and pathophysiology. Domest Anim Endocrinol 2016; 56 Suppl:S66-83. [PMID: 27345325 DOI: 10.1016/j.domaniend.2016.02.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 02/11/2016] [Accepted: 02/15/2016] [Indexed: 02/08/2023]
Abstract
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are 2 biologically active peptides produced by the same gene, ADM, with ubiquitous distribution and many physiological functions. Adrenomedullin is composed of 52 amino acids, has an internal molecular ring composed by 6 amino acids and a disulfide bond, and shares structural similarities with calcitonin gene-related peptide, amylin, and intermedin. The AM receptor consists of a 7-transmembrane domain protein called calcitonin receptor-like receptor in combination with a single transmembrane domain protein known as receptor activity-modifying protein. Using morphologic techniques, it has been shown that AM and PAMP are expressed throughout the gastrointestinal tract, being specially abundant in the neuroendocrine cells of the gastrointestinal mucosa; in the enterochromaffin-like and chief cells of the gastric fundus; and in the submucosa of the duodenum, ileum, and colon. This wide distribution in the gastrointestinal tract suggests that AM and PAMP may act as gut hormones regulating many physiological and pathologic conditions. To date, it has been proven that AM and PAMP act as autocrine/paracrine growth factors in the gastrointestinal epithelium, play key roles in the protection of gastric mucosa from various kinds of injury, and accelerate healing in diseases such as gastric ulcer and inflammatory bowel diseases. In addition, both peptides are potent inhibitors of gastric acid secretion and gastric emptying; they regulate the active transport of sugars in the intestine, regulate water and ion transport in the colon, modulate colonic bowel movements and small-intestine motility, improve endothelial barrier function, and stabilize circulatory function during gastrointestinal inflammation. Furthermore, AM and PAMP are antimicrobial peptides, and they contribute to the mucosal host defense system by regulating gut microbiota. To get a formal demonstration of the effects that endogenous AM and PAMP may have in gut microbiota, we developed an inducible knockout of the ADM gene. Using this model, we have shown, for the first time, that lack of AM/PAMP leads to changes in gut microbiota composition in mice. Further studies are needed to investigate whether this lack of AM/PAMP may have an impact in the development and/or progression of intestinal diseases through their effect on microbiota composition.
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Affiliation(s)
- S Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, La Rioja 26006, Spain
| | - A Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, La Rioja 26006, Spain.
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Adrenomedullin: A potential therapeutic target for retinochoroidal disease. Prog Retin Eye Res 2016; 52:112-29. [DOI: 10.1016/j.preteyeres.2016.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 01/06/2016] [Accepted: 01/07/2016] [Indexed: 11/22/2022]
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Kawano S, Kawagoe Y, Kuwasako K, Shimamoto S, Igarashi K, Tokashiki M, Kitamura K, Kato J. Gender-related alterations in plasma adrenomedullin level and its correlation with body weight gain. Endocr Connect 2015; 4:43-9. [PMID: 25573159 PMCID: PMC4312856 DOI: 10.1530/ec-14-0131] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Plasma levels of adrenomedullin (AM), a bioactive peptide produced in adipose tissue, have been shown to be higher in obese patients than in non-obese patients, but little is known about gender differences in plasma AM levels. The aims of this study were to clarify gender-related alterations in plasma AM levels and to examine the body weight (BW) gain-plasma AM relationship in the general population. We measured plasma AM levels of 346 local residents (62.0±8.9 years, mean±s.d.) in the Kiyotake area, Japan, who underwent a regular health check-up, by a specific fluorescence immunoassay. Plasma AM levels in the female residents were lower than that in the males, and multiple regression analysis revealed a possible gender difference in plasma AM. The AM levels were significantly correlated with BMI or waist circumference in women, but such a relationship was not seen in men. When the subjects were divided into two groups by results of a questionnaire about BW gain of 10 kg or more since the age of 20 years, the plasma AM level of women with BW gain ≧10 kg was significantly higher than that in those without BW gain, although no difference was noted between the men with and without BW gain. In conclusion, possible gender differences were noted in the plasma AM levels and in the BW gain-plasma AM relationship in the general population. The plasma AM levels in the female residents without BW gain seem partly attributable to the lower AM of women.
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Affiliation(s)
- Sayaka Kawano
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Yukiko Kawagoe
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Kenji Kuwasako
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Satoshi Shimamoto
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Koji Igarashi
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Mariko Tokashiki
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Kazuo Kitamura
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Johji Kato
- Frontier Science Research CenterCirculatory and Body Fluid RegulationDepartment of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanAIA Research GroupBioscience Division, Reagent Development Department, TOSOH Corporation, Kanagawa 252-1123, Japan
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Larráyoz IM, Martínez-Herrero S, García-Sanmartín J, Ochoa-Callejero L, Martínez A. Adrenomedullin and tumour microenvironment. J Transl Med 2014; 12:339. [PMID: 25475159 PMCID: PMC4272513 DOI: 10.1186/s12967-014-0339-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/21/2014] [Indexed: 01/03/2023] Open
Abstract
Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed.
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Affiliation(s)
- Ignacio M Larráyoz
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Sonia Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Josune García-Sanmartín
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
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8
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Wong HK, Tang F, Cheung TT, Cheung BMY. Adrenomedullin and diabetes. World J Diabetes 2014; 5:364-371. [PMID: 24936257 PMCID: PMC4058740 DOI: 10.4239/wjd.v5.i3.364] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Adrenomedullin (ADM) is a peptide hormone widely expressed in different tissues, especially in the vasculature. Apart from its vasodilatatory and hypotensive effect, it plays multiple roles in the regulation of hormonal secretion, glucose metabolism and inflammatory response. ADM regulates insulin balance and may participate in the development of diabetes. The plasma level of ADM is increased in people with diabetes, while in healthy individuals the plasma ADM concentration remains low. Plasma ADM levels are further increased in patients with diabetic complications. In type 1 diabetes, plasma ADM level is correlated with renal failure and retinopathy, while in type 2 diabetes its level is linked with a wider range of complications. The elevation of ADM level in diabetes may be due to hyperinsulinemia, oxidative stress and endothelial injury. At the same time, a rise in plasma ADM level can trigger the onset of diabetes. Strategies to reduce ADM level should be explored so as to reduce diabetic complications.
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Suchetha A, Garg A, Lakshmi P, Bhat D, Sapna N, Apoorva SM. Adrenomedullin, periodontitis, diabetes-unraveling the equivocal relationship: A clinicobiochemical cross-sectional study. Contemp Clin Dent 2014; 4:454-9. [PMID: 24403788 PMCID: PMC3883323 DOI: 10.4103/0976-237x.123040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Context: Antimicrobial proteins and peptides constitute a diverse class of host-defense molecules that act early to combat invasion and infection with bacteria and other microorganisms. Among the various antimicrobial peptides in the oral cavity, adrenomedullin (ADM), a cationic peptide, is found in gingival crevicular fluids (GCFs) in amounts twice as high in periodontal disease sites as healthy sites. Studies have also shown that plasma levels of ADM increased in patients with type 2 diabetes mellitus as compared with controls. Aims: This clinico-biochemical study was undertaken to try to decipher the probable link between ADM, diabetes and periodontitis. Materials and Methods: The study comprised of 90 patients who were divided into three groups based on community periodontal index scores and diabetes status. Probing pocket depth and clinical attachment level were measured in all subjects. GCF was collected from all the participants using micropipettes and blood samples were collected from subjects in Groups III, for analysis of glycated hemoglobin. ADM levels were measured in GCF samples by the enzyme-linked immunosorbent assay. Statistical Analysis Used: The data obtained were subjected to analysis of variance, Bonferroni test and Pearson's correlation. Results: An increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes was noted. Conclusions: Increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes reinforces the perio-systemic interlink concept.
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Affiliation(s)
- A Suchetha
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
| | - Akanksha Garg
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
| | - P Lakshmi
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
| | - Divya Bhat
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
| | - N Sapna
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
| | - S M Apoorva
- Department of Periodontics, DAPM RV Dental College, Bengaluru, Karnataka, India
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Plasma levels of IL-17, VEGF, and adrenomedullin and S-cone dysfunction of the retina in children and adolescents without signs of retinopathy and with varied duration of diabetes. Mediators Inflamm 2013; 2013:274726. [PMID: 24347823 PMCID: PMC3852315 DOI: 10.1155/2013/274726] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 10/06/2013] [Accepted: 10/12/2013] [Indexed: 11/30/2022] Open
Abstract
The study objective was to assess chosen biochemical parameters of blood and bioelectric function of the retina in patients with T1DM. The study group consisted of 41 patients with T1DM with no signs of diabetic retinopathy. The control group included 21 pediatric patients. We performed (1) S-cone ERG testing with retina response stimulation in both eyes at the luminance of 0.1, 0.2, and 0.5 (cd × s/m2) with the 440 nm blue flash and light application of the amber background (300 ph cd/m2, 495 nm wavelength), (2) anthropometric measurements, (3) biochemical investigations: IL-17, VEGF, and ADM by the ELISA method. A comparison of the ERG results with biochemical investigations indicates a likely correlation between the worsening of retinal bioelectric function and VEGF levels growing with diabetes duration. We showed a negative correlation between ADM and HbA1c and described possible causes of ADM reduction observed in subgroup I. We demonstrated the presence of bioelectric retinal dysfunction already before the diagnosis of diabetic retinopathy, which provides new possibilities in the diagnosis of preclinical chronic complications of diabetes. The changes observed in the levels of IL-17, ADM, and VEGF suggest their involvement in the diabetic pathogenesis of eye diseases.
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11
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Ertugrul AS, Dikilitas A, Sahin H, Alpaslan NZ, Bozoglan A. Gingival crevicular fluid adrenomedullin level in individuals with and without diabetes mellitus type 2. J Periodontal Res 2012; 48:342-9. [DOI: 10.1111/jre.12013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2012] [Indexed: 11/29/2022]
Affiliation(s)
- A. S. Ertugrul
- Department of Periodontology; Faculty of Dentistry; Yuzuncu Yil University; Van Turkey
| | - A. Dikilitas
- Department of Periodontology; Faculty of Dentistry; Yuzuncu Yil University; Van Turkey
| | - H. Sahin
- Department of Periodontology; Faculty of Dentistry; Yuzuncu Yil University; Van Turkey
| | - N. Z. Alpaslan
- Department of Periodontology; Faculty of Dentistry; Yuzuncu Yil University; Van Turkey
| | - A. Bozoglan
- Department of Periodontology; Faculty of Dentistry; Yuzuncu Yil University; Van Turkey
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Blom JJ, Giove TJ, Favazza TL, Akula JD, Eldred WD. Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy. J Ocul Biol Dis Infor 2012; 4:70-82. [PMID: 23316263 DOI: 10.1007/s12177-011-9072-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 12/05/2011] [Indexed: 12/18/2022] Open
Abstract
The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.
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Affiliation(s)
- Jan J Blom
- Department of Biology, Boston University, Boston, MA USA
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Zhang J, Zhang BH, Yu YR, Tang CS, Qi YF. Adrenomedullin protects against fructose-induced insulin resistance and myocardial hypertrophy in rats. Peptides 2011; 32:1415-21. [PMID: 21664393 DOI: 10.1016/j.peptides.2011.05.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 05/25/2011] [Accepted: 05/25/2011] [Indexed: 01/13/2023]
Abstract
Adrenomedullin (ADM) has been recognized as a multipotent multifunctional peptide. To explore the pathophysiological roles of ADM in insulin resistance (IR), we studied the changes in ADM mRNA level in the myocardium and vessels and the effect of ADM supplementation on rats with IR induced by fructose feeding. Rats were fed 4% fructose in drinking water for 8 weeks, and ADM was administered subcutaneously in pure water through an Alzet Mini-osmotic Pump at 300 ng/kg/h for the last 4 weeks. Compared with controls, rats with IR showed increased levels of fasting blood sugar and serum insulin, by 95% and 67%, respectively (all P<0.01), and glycogen synthesis and glucose transport activity of the soleus decreased by 54% and 55% (all P<0.01). mRNA level and content of brain natriuretic peptide (BNP) in myocardial were all increased significantly. Fructose-fed rats showed increased immunoreactive-ADM content in plasma by 110% and in myocardia by 55% and increased mRNA level in myocardia and vessels (all P<0.01). ADM administration ameliorated the induced IR and myocardial hypertrophy. The glycogen synthesis and glucose transport activity of the soleus muscle increased by 41% (P<0.01) and 32% (P<0.05). ADM therapy attenuated myocardial and soleus lipid peroxidation injury and enhanced the antioxidant ability. Our results showed upregulation of endogenous ADM during fructose-induced IR and the protective effect of ADM on fructose-induced IR and concomitant cardiovascular hypertrophy probably by its antioxidant effect, which suggests that ADM could be an endogenous protective factor in IR.
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Affiliation(s)
- Jing Zhang
- School of P.E. and Sports Science, Beijing Normal University, Beijing 100875, China
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14
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El-Habashy SA, Matter RM, El-Hadidi ES, Afifi HR. Plasma adrenomedullin level in Egyptian children and adolescents with type 1 diabetes mellitus: relationship to microvascular complications. Diabetol Metab Syndr 2010; 2:12. [PMID: 20181139 PMCID: PMC2834643 DOI: 10.1186/1758-5996-2-12] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Accepted: 02/10/2010] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Adrenomedullin (AM) is known to be elevated in different clinical situations including diabetes mellitus (DM), but its potential role in the pathogenesis of vascular complications in diabetic children and adolescents is to be clarified. Hence, the study aimed at assessment of plasma adrenomedullin levels in children and adolescents with type 1 DM and correlation of these levels with metabolic control and diabetic microvascular complications (MVC). METHODS The study was performed in the Diabetes Specialized Clinic, Children's Hospital of Ain Shams University in Cairo, Egypt. It included 55 diabetic children and adolescents (mean age 13.93 +/- 3.15 years) who were subdivided into 40 with no MVC and 15 with MVC. Thirty healthy subjects, age-and sex-matched, were included as control group (mean age 12.83 +/- 2.82 years). Patients and controls were assessed for glycosylated hemoglobin (HbA1c) and plasma adrenomedullin assay using ELISA technique. RESULTS Mean plasma AM levels were significantly increased in patients with and without MVC compared to control group, (110.6 pg/mL, 60.25 pg/mL and 39.2 pg/mL respectively) (P < 0.01) with higher levels in those with MVC (P < 0.05). Plasma AM levels were positively correlated with both duration of diabetes (rho = 0.703, P < 0.001) and glycemic control (HbA1c) (rho = 0.453, P < 0.001). CONCLUSION Higher plasma AM levels in diabetics particularly in those with MVC & its correlation with diabetes duration and metabolic control may reflect the role of AM in diabetic vasculopathy in the pediatric age group.
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Affiliation(s)
- Safinaz A El-Habashy
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Randa M Matter
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Eman S El-Hadidi
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Hala R Afifi
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
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15
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Al-Omari MA, Khaleghi M, Mosley TH, Turner ST, Morgenthaler NG, Struck J, Bergmann A, Kullo IJ. Mid-regional pro-adrenomedullin is associated with pulse pressure, left ventricular mass, and albuminuria in African Americans with hypertension. Am J Hypertens 2009; 22:860-6. [PMID: 19424162 PMCID: PMC2864024 DOI: 10.1038/ajh.2009.82] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND African Americans with hypertension are prone to target-organ damage and adverse cardiovascular events. Biomarkers for early detection of target-organ damage in this ethnic group are needed. Adrenomedullin (ADM) is a circulating vasoactive peptide with vasodilatory and antiproliferative effects that has been reported to be elevated in adults with hypertension. METHODS We investigated the associations of plasma levels of mid-regional pro-ADM (MR-proADM) with pulse pressure, left ventricular mass (LVM), and albuminuria in 1,034 African-American adults (65 +/- 9 years, 72% women) with hypertension. MR-proADM was measured by an immunoluminometric assay, LVM was assessed by 2-dimensional echocardiography, and albuminuria was assessed by urine albumin:creatinine ratio (UACR). Multivariable regression analyses were used to assess whether plasma MR-proADM was independently associated with pulse pressure, LVM indexed by height to the power 2.7 (LVMi), and UACR. RESULTS Plasma MR-proADM was significantly correlated (P < 0.001) with pulse pressure, LVMi, and UACR. In separate multivariable linear regression models that adjusted for age and sex, log MR-proADM was associated with greater pulse pressure (P = 0.007), log LVMi (P = 0.001), and log (UACR+1) (P < 0.0001). After additional adjustment for body mass index (BMI), total and high-density lipoprotein (HDL) cholesterol, smoking history, diabetes, estimated glomerular filtration rate (eGFR), history of myocardial infarction (MI) or stroke, and medication use, log MR-proADM remained significantly associated with greater pulse pressure (P = 0.001), log LVMi (P = 0.029), and log (UACR+1) (P = 0.002). CONCLUSIONS In African-American adults with hypertension, plasma MR-proADM is independently associated with pulse pressure, LVMi, and albuminuria and is a potential biomarker for target organ damage.
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Affiliation(s)
| | - Mahyar Khaleghi
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | - Thomas H. Mosley
- Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS
| | | | | | - Joachim Struck
- Research Department, BRAHMS Aktiengesellschaft, Hennigsdorf, Germany
| | - Andreas Bergmann
- Research Department, BRAHMS Aktiengesellschaft, Hennigsdorf, Germany
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16
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Correlation of electroretinography b-wave absolute latency, plasma levels of human basic fibroblast growth factor, vascular endothelial growth factor, soluble fatty acid synthase, and adrenomedullin in diabetic retinopathy. J Diabetes Complications 2009; 24:179-85. [PMID: 19216096 DOI: 10.1016/j.jdiacomp.2008.12.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2008] [Revised: 10/24/2008] [Accepted: 12/22/2008] [Indexed: 10/21/2022]
Abstract
BACKGROUND We investigated the b-wave latency of electroretinogram (ERG), human basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), soluble fatty acid synthase (s-Fas), and adrenomedullin (ADM) in diabetic retinopathy. PATIENTS AND METHODS Thirty control and 60 type II diabetic women (mean age 45+/-3.9 years, duration of diabetes 10.1+/-2.1 years) were investigated. Diabetics without complications (Group II) and with retinopathy (Group III) were diagnosed depending on clinical findings, abnormal fundus examination, and ERG. Plasma levels of b-FGF, VEGF, s-Fas, and ADM were measured. RESULTS ERG showed a significant increase of b-wave absolute latency, plasma b-FGF, VEGF, s-Fas, and ADM in diabetic retinopathy (P<.05). A positive correlation was found between b-wave latency and VEGF and s-Fas, and a negative correlation with b-FGF and ADM. CONCLUSION This study elucidates the causative role of VEGF and s-Fas in diabetic retinopathy. VEGF may potently promote growth of endothelial cells and formation of new vessels implicated in proliferative retinopathy. s-Fas could be involved in advancement of apoptotic changes in retinopathy and high levels of b-FGF, and ADM may be compensatorily neuroprotective and vasculoprotective. The results showed that diabetic retinopathy is the result of multiple factors, so it is optimistic to believe that reversing VEGF or s-Fas will halt retinopathy, targeting multiple mechanisms simultaneously by administering combination treatments of VEGF antagonists; antiapoptotic drugs together with b-FGF and/or ADM may be prospective.
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17
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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 2007; 30:1513-9. [PMID: 17384335 DOI: 10.2337/dc06-1899] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel vascoactive factor, is deranged in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Using a new immunoluminometric method, plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese subjects: healthy (n = 100, fasting plasma glucose [FPG] <5.6 mmol/l), impaired fasting glucose (IFG) (n = 60, FPG 5.6-6.9 mmol/l), and diabetic subjects with (n = 100) and without (n = 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quantified in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function. RESULTS We observed a stepwise increase in MR-proADM among the groups: healthy group mean +/- SD 0.27 +/- 0.09, IFG group 0.29 +/- 0.13, diabetic group 0.42 +/- 0.13, and diabetic nephropathy group 0.81 +/- 0.54 nmol/l (diabetic vs. healthy and IFG groups, P = 0.04; and diabetic nephropathy group vs. all, P < 0.01). Statistical adjustment for sex, age, BMI, and blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (beta = 0.11; P = 0.01), insulin resistance index (beta = 0.20; P = 0.001), LDL cholesterol (beta = 0.31; P < 0.001), and adiponectin (beta = 0.33; P < 0.001) were significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with RCMP (r = 0.43, P = 0.002). CONCLUSIONS Plasma MR-proADM concentration was elevated in subjects with type 2 diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a role in the pathogenesis of diabetic vasculopathy.
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Affiliation(s)
- Su Chi Lim
- Department of Medicine, Alexandra Hospital, Singapore, Republic of Singapore.
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18
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Changes in expression of adrenomedullin in the myocardium of streptozotocin-induced diabetic rats. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200702010-00003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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19
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Goralski KB, Sinal CJ. Type 2 diabetes and cardiovascular disease: getting to the fat of the matterThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum. Can J Physiol Pharmacol 2007; 85:113-32. [PMID: 17487251 DOI: 10.1139/y06-092] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990’s revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.
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Affiliation(s)
- Kerry B Goralski
- College of Pharmacy, Department of Pharmacology, Dalhousie University, Halifax, NS B3H 1X5, Canada
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20
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García MA, Martín-Santamaría S, de Pascual-Teresa B, Ramos A, Julián M, Martínez A. Adrenomedullin: a new and promising target for drug discovery. Expert Opin Ther Targets 2006; 10:303-17. [PMID: 16548778 DOI: 10.1517/14728222.10.2.303] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.
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Affiliation(s)
- Mario A García
- Universidad San Pablo CEU, Departamento de Química, Facultad de Farmacia, Urbanización Montepríncipe, 28668 Boadilla del Monte, Madrid, Spain
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21
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Huang H, Ma C, Yang M, Tang C, Wang H. Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells. Cell Physiol Biochem 2005; 15:117-24. [PMID: 15665522 DOI: 10.1159/000083644] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2004] [Indexed: 12/15/2022] Open
Abstract
Adrenomedullin (AM) was originally identified as a vasodilator peptide, and has recently been shown to be an antiproliferative factor in renal mesangial cells, suggesting that adrenomedullin may impair the progression of glomerulosclerosis. This study was to investigate the effect of adrenomedullin on transforming growth factor-beta1 (TGF-beta1)-stimulated cell growth, synthesis of extracellular matrix (ECM) components and the related molecular mechanism in a human tubular epithelial cell line HK-2. TGF-beta1 inhibited cell proliferation induced by fetal bovine serum, but neither AM itself affectted cell proliferation, nor did AM influence TGF-beta1-caused cell growth arrest. However, AM beginning at 10(-8) M alleviated the action of TGF-beta1-stimulated cellular collagen synthesis and secretion of fibronectin into cell culture supernatant. Activation of Smad proteins is known to be the key signaling pathway of the profibrotic effect of TGF-beta1, AM at 10(-8) M exerted no effect on TGF-beta1-induced Smad2 phosphorylation, but prevented the suppression of the inhibitory Smad6 protein by TGF-beta1 and restored Smad2-Samd6 complex formation. Our results suggest that AM can attenuate TGF-beta1-mediated renal tubulointerstitial ECM turnover via an antagonistic mechanism of inhibitory Smad in TGF-beta1-elicited signaling.
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Affiliation(s)
- Haichang Huang
- Division of Nephrology, Peking University First Hospital and Institute of Nephrology, China
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22
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García-Unzueta MT, Berrazueta JR, Pesquera C, Obaya S, Fernández MD, Sedano C, Amado JA. Levels of plasma total adrenomedullin are related with two acute phase inflammatory reactants (fibrinogen and sialic acid) but not with markers of endothelial dysfunction in Type 1 diabetes Adrenomedullin and vascular risk factors in Type 1 DM. J Diabetes Complications 2005; 19:147-54. [PMID: 15866060 DOI: 10.1016/j.jdiacomp.2004.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2004] [Revised: 08/26/2004] [Accepted: 08/31/2004] [Indexed: 10/25/2022]
Abstract
Adrenomedullin (AM), an ubiquitous regulatory peptide with different actions, is known to be elevated in different clinical situations, including diabetes mellitus (DM), but its potential role in the pathogenesis of diabetic vascular complications is not clear. In the present study, we examined plasma total AM levels, and their association with different markers of endothelial dysfunction and with other established risk factors for cardiovascular diseases, in patients with Type 1 DM. We studied a total of 155 patients, 117 patients without any kind of vascular complications, 24 patients with retinopathy only, and 14 patients with retinopathy and microalbuminuria but normal renal function. None of them had clinical evidence of atherosclerotic disease. Compared with the control group (64 healthy participants), patients had raised fibrinogen, soluble E-selectin ((s)E-selectin), vascular cellular adhesion molecule (VCAM), angiotensin converting enzyme (ACE), and von Willebrand factor (vWf) (P<.001 in all cases), but plasma total AM, endothelin (ET), sialic acid, and homocysteine were not raised. In the diabetic group, AM levels correlated significantly with sialic acid (r=.16; P<.05), but a more significant correlation was found with fibrinogen (r=.30; P<.001). No correlation was found with the other parameters studied. In summary, plasma total AM levels seem to correlate with inflammatory markers but not with endothelial dysfunction markers in Type 1 diabetic patients without atherosclerotic disease.
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Affiliation(s)
- M T García-Unzueta
- Endocrinology Service, Endocrine Unit, Hospital Universitario M. de Valdecilla, Valdecilla Street, Santander 39008, Spain
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23
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Er H, Doğanay S, Ozerol E, Yürekli M. Adrenomedullin and Leptin Levels in Diabetic Retinopathy and Retinal Diseases. Ophthalmologica 2005; 219:107-11. [PMID: 15802936 DOI: 10.1159/000083270] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2003] [Accepted: 06/11/2004] [Indexed: 12/21/2022]
Abstract
PURPOSE Proliferative and vascular retinal diseases are important cause of irreversible blindness. Consistent features of these diseases are endothelial dysfunction and angiogenesis. Adrenomedullin (ADM) is a multifunctional vasorelaxant peptide. Leptin is a recently discovered metabolic peptide that regulates energy metabolism in human. In the present study, we aimed to investigate the possible roles of adrenomedullin and leptin in the pathophysiology of diabetic and proliferative diseases. METHODS Ten patients with proliferative diabetic retinopathy (57.1 years, 5 female and 5 male) and 8 patients (51 years, 5 female and 3 male) with other retinal diseases including macular hole and epiretinal membrane were included in this study. All the patients had undergone pars plana vitrectomy for complications of the diseases. Vitreous samples were collected by vitreous tap during the vitrectomy. Adrenomedullin analysis was made by using reverse-phase high-performance liquid chromatography (HPLC). Leptin was measured by enzyme-linked immunosorbent assay (ELISA). Body mass index (BMI) [weight (kg)/height (m2)] was calculated for each group. The Mann-Whitney U test was used for statistics. RESULTS The age, gender ratio and BMI were not substantially different between the two groups. The mean vitreous adrenomedullin levels (63.9+/-7.1 pmol/l) were significantly higher (p<0.05) in group I than in group II (34.25+/-3.0 pmol/l). Leptin levels in vitreous (4.54+/-1.6 ng/ml) were also significantly higher (p<0.05) in patients with diabetic retinopathy than in those without diabetes (1.83+/-0.5 ng/ml). CONCLUSION Increased adrenomedullin and leptin levels in vitreous humor might be a possible newly associated factor in the course of vascular and proliferative retinal diseases.
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Affiliation(s)
- Hamdi Er
- Department of Ophthalmology, Inonu University Turgut Ozal Medical Center, Malatya, Turkey.
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Bomberger JM, Parameswaran N, Hall CS, Aiyar N, Spielman WS. Novel Function for Receptor Activity-modifying Proteins (RAMPs) in Post-endocytic Receptor Trafficking. J Biol Chem 2005; 280:9297-307. [PMID: 15613468 DOI: 10.1074/jbc.m413786200] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
RAMPs (1-3) are single transmembrane accessory proteins crucial for plasma membrane expression, which also determine receptor phenotype of various G-protein-coupled receptors. For example, adrenomedullin receptors are comprised of RAMP2 or RAMP3 (AM1R and AM2R, respectively) and calcitonin receptor-like receptor (CRLR), while a CRLR heterodimer with RAMP1 yields a calcitonin gene-related peptide receptor. The major aim of this study was to determine the role of RAMPs in receptor trafficking. We hypothesized that a PDZ type I domain present in the C terminus of RAMP3, but not in RAMP1 or RAMP2, leads to protein-protein interactions that determine receptor trafficking. Employing adenylate cyclase assays, radioligand binding, and immunofluorescence microscopy, we observed that in HEK293 cells the CRLR-RAMP complex undergoes agonist-stimulated desensitization and internalization and fails to resensitize (i.e. degradation of the receptor complex). Co-expression of N-ethylmaleimide-sensitive factor (NSF) with the CRLR-RAMP3 complex, but not CRLR-RAMP1 or CRLR-RAMP2 complex, altered receptor trafficking to a recycling pathway. Mutational analysis of RAMP3, by deletion and point mutations, indicated that the PDZ motif of RAMP3 interacts with NSF to cause the change in trafficking. The role of RAMP3 and NSF in AM2R recycling was confirmed in rat mesangial cells, where RNA interference with RAMP3 and pharmacological inhibition of NSF both resulted in a lack of receptor resensitization/recycling after agonist-stimulated desensitization. These findings provide the first functional difference between the AM1R and AM2R at the level of post-endocytic receptor trafficking. These results indicate a novel function for RAMP3 in the post-endocytic sorting of the AM-R and suggest a broader regulatory role for RAMPs in receptor trafficking.
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Affiliation(s)
- Jennifer M Bomberger
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA
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Bunton DC, Petrie MC, Hillier C, Johnston F, McMurray JJV. The clinical relevance of adrenomedullin: a promising profile? Pharmacol Ther 2005; 103:179-201. [PMID: 15464589 DOI: 10.1016/j.pharmthera.2004.07.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.
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Affiliation(s)
- David C Bunton
- Vascular Assessment Unit, Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, UK.
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Fukai N, Yoshimoto T, Sugiyama T, Ozawa N, Sato R, Shichiri M, Hirata Y. Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues. Am J Physiol Endocrinol Metab 2005; 288:E56-62. [PMID: 15315911 DOI: 10.1152/ajpendo.00586.2003] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Adrenomedullin (AM) expressed by and secreted from a variety of cells plays pluripotent roles in an autocrine/paracrine fashion. The present study was undertaken to explore the expression of AM and its receptor genes in adipose tissues, their changes during the development of obesity, and the process of preadipocyte differentiation. Both mature adipocytes and stromal vascular cells constituting adipose tissue expressed AM transcript. AM and its receptor component [calcitonin receptor-like receptor and receptor activity-modifying protein-2 (CRLR/RAMP2)] mRNAs were expressed in a variety of rat adipose tissues, including epididymal, mesenteric, retroperitoneal, and subcutaneous adipose tissue. AM mRNA levels in rat and human epididymal adipose tissue were about one-tenth of those in the kidney. Steady-state mRNA levels of AM and CRLR/RAMP2 in epididymal, mesenteric, and retroperitoneal adipose tissues in rats fed a high-fat diet for 4 wk were far greater than those in rats with normal diet accompanied by increased plasma AM levels, whereas steady-state AM mRNA levels conversely decreased in other organs, such as kidney and liver. AM mRNA expressed in a mouse preadipocyte cell line (3T3-L1) transiently decreased by day 3, returned to basal level by day 6, and then increased by day 9 during preadipocyte differentiation, which paralleled AM secretion from the cells. However, the addition of either exogenous AM or AM receptor antagonist calcitonin gene-related peptide-(8-37), to block endogenous AM did not affect lipid droplet accumulation during preadipocyte differentiation. The present study demonstrates for the first time that AM and its receptor component (CRLR/RAMP2) mRNAs were concomitantly expressed in various adipose tissues, whose tissue-specific upregulation was induced during the development of obesity. These data suggest that AM may act as a new member of adipokines, although its functional role, as well as its pathophysiological significance in obesity, remains to be determined.
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Affiliation(s)
- Nozomi Fukai
- Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8513, Japan
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Hiragushi K, Wada J, Eguchi J, Matsuoka T, Yasuhara A, Hashimoto I, Yamashita T, Hida K, Nakamura Y, Shikata K, Minamino N, Kangawa K, Makino H. The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. Kidney Int 2004; 65:540-50. [PMID: 14717924 DOI: 10.1111/j.1523-1755.2004.00407.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. METHODS Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. RESULTS STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. CONCLUSION Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.
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MESH Headings
- Adrenomedullin
- Animals
- Aorta/cytology
- Blood Glucose/metabolism
- Blotting, Northern
- Cells, Cultured
- DNA, Antisense
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/physiopathology
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/pathology
- Diabetic Nephropathies/physiopathology
- Endothelium, Vascular/cytology
- Gene Expression
- Humans
- Hypertrophy
- Intracellular Signaling Peptides and Proteins
- Kidney Glomerulus/metabolism
- Kidney Glomerulus/pathology
- Kidney Glomerulus/physiopathology
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Nitrates/urine
- Nitric Oxide/metabolism
- Nitric Oxide Synthase/metabolism
- Nitric Oxide Synthase Type III
- Nitrites/urine
- Peptides/blood
- Peptides/genetics
- Peptides/urine
- RNA, Messenger/analysis
- Rats
- Rats, Sprague-Dawley
- Receptor Activity-Modifying Protein 2
- Receptor Activity-Modifying Protein 3
- Receptor Activity-Modifying Proteins
- Receptors, Adrenomedullin
- Receptors, Peptide/genetics
- Receptors, Peptide/metabolism
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Affiliation(s)
- Keita Hiragushi
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
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Suzuki Y, Horio T, Nonogi H, Hayashi T, Kitamura K, Eto T, Kangawa K, Kawano Y. Adrenomedullin as a sensitive marker for coronary and peripheral arterial complications in patients with atherosclerotic risks. Peptides 2004; 25:1321-6. [PMID: 15350700 DOI: 10.1016/j.peptides.2004.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2004] [Revised: 04/23/2004] [Accepted: 04/23/2004] [Indexed: 11/26/2022]
Abstract
Plasma adrenomedullin (AM) levels are elevated in various pathological states including cardiovascular and inflammatory diseases. The present study investigated whether an increased AM level is a marker of vascular complications in patients with atherosclerotic risks. In 114 patients with cardiovascular risks and/or diseases including ischemic heart disease (IHD) and peripheral arterial disease (PAD), plasma AM concentration and other inflammatory markers such as high sensitive C-reactive protein (CRP) and interleukin (IL)-6 were examined. The plasma AM level was not altered by the absence or presence of each of four major risk factors, i.e., hypertension, diabetes mellitus, hyperlipidemia, and smoking and its level was not significantly correlated with blood pressure, plasma glucose, or serum lipid levels. The patients with IHD had a significantly higher concentration of plasma AM than those without IHD. The AM level in subjects with PAD was also increased significantly compared with those without PAD. The plasma AM was strongly correlated with inflammatory parameters such as CRP and IL-6. Among AM, CRP, and IL-6, however, only AM was an independent predictor for both IHD and PAD by multiple logistic regression analysis. Our findings suggest the possibility that plasma AM is a novel sensitive marker for the presence of vascular lesions in patients with atherosclerotic risks.
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Affiliation(s)
- Yoshihiko Suzuki
- Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan
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29
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Oehler MK, Fischer DC, Orlowska-Volk M, Herrle F, Kieback DG, Rees MCP, Bicknell R. Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer. Br J Cancer 2004; 89:1927-33. [PMID: 14612905 PMCID: PMC2394432 DOI: 10.1038/sj.bjc.6601397] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Adrenomedullin (ADM) is an angiogenic factor that has also been shown to be a mitogen and a hypoxia survival factor for tumour cells. These properties point to ADM as a potential promoter of human malignancies, but little data are available concerning the expression of ADM in human breast cancer. In the present work, we have examined ADM peptide expression in a series of malignant breast tumours by immunohistochemistry using a newly developed anti-ADM monoclonal antibody. In addition, ADM plasma concentrations in breast cancer patients and healthy controls were determined by radioimmunoassay. Of the examined breast cancer samples, 27/33 (82%) showed a moderate to strong staining intensity. ADM-peptide expression in breast tumours was significantly correlated with axillary lymph node metastasis (P=0.030). Analysis of ADM plasma concentrations showed no significant difference between the circulating ADM levels of breast cancer patients and healthy controls. However, a significant positive correlation was found between tumour size and plasma ADM levels (r=0.641, P=0.017). Moreover, ADM levels in breast cancer patients correlated with the presence of lymph node metastasis (P=0.002). In conclusion, we have shown for the first time that ADM peptide is widely expressed in breast cancer and that the degree of expression is associated with lymph node metastasis. ADM peptide in plasma of breast cancer patients reflects the size of the primary tumour, but is unlikely to be a useful tumour marker for the detection of breast cancer. Plasma ADM might represent an independent predictor of lymph node metastasis. The clinical implications of these findings remain to be evaluated.
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Affiliation(s)
- M K Oehler
- Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
- Department of Obstetrics & Gynaecology, University of Freiburg, D-79106 Freiburg, Germany
| | - D C Fischer
- Department of Obstetrics & Gynaecology, University of Freiburg, D-79106 Freiburg, Germany
| | - M Orlowska-Volk
- Department of Pathology, University of Freiburg, D-79106 Freiburg, Germany
| | - F Herrle
- Department of Obstetrics & Gynaecology, University of Freiburg, D-79106 Freiburg, Germany
| | - D G Kieback
- Department of Obstetrics & Gynaecology, University of Freiburg, D-79106 Freiburg, Germany
| | - M C P Rees
- Nuffield Department of Obstetrics & Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - R Bicknell
- Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
- Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. E-mail:
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30
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López J, Martínez A. Cell and molecular biology of the multifunctional peptide, adrenomedullin. INTERNATIONAL REVIEW OF CYTOLOGY 2003; 221:1-92. [PMID: 12455746 DOI: 10.1016/s0074-7696(02)21010-4] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Adrenomedullin (AM) is a recently discovered regulatory peptide involved in many functions including vasodilatation, electrolyte balance, neurotransmission, growth, and hormone secretion regulation, among others. This 52-amino acid peptide is expressed by specific cell types in many organs throughout the body. A complex receptor system has been described for AM; it requires at least the presence of a seven-transmembrane-domain G-protein-coupled receptor, a single-transmembrane-domain receptor activity modifying protein, and a receptor component protein needed to establish the connection with the downstream signal transduction pathway, which usually involves cyclicAMP. In addition, a serum-binding protein regulates the biological actions of AM, frequently by increasing AM functional attributes. Changes in levels of circulating AM correlate with several critical diseases, including cardiovascular and renal disorders, sepsis, cancer, and diabetes. Whether AM is a causal agent, a protective reaction, or just a marker for these diseases is currently under investigation. New technologies seeking to elevate and/or reduce AM levels are being investigated as potential therapeutic avenues.
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Affiliation(s)
- José López
- Cell Biology Unit, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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31
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Di Iorio R, Marinoni E, Letizia C, Cosmi EV. Adrenomedullin in perinatal medicine. REGULATORY PEPTIDES 2003; 112:103-13. [PMID: 12667631 DOI: 10.1016/s0167-0115(03)00028-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
This review will consider whether adrenomedullin (AM) plays a role in the different aspects of perinatal medicine: contributing to maternal systemic vasodilatation during pregnancy, regulating uterine and placental blood flow, being involved in the process of implantation and participating in uterine quiescence prior to parturition. In addition, this will also consider whether a modification of AM secretion contributes to some pathological conditions in pregnancy such as preeclampsia and impairment of fetal growth. The biosynthesis of AM increases in gravid rats and in pregnant women, and the placenta represents an important site of AM production during pregnancy. Both the peptide and its receptors have been found in the uterus, placenta, fetal membranes and cord vessels, and fetal membranes and placental tissues in culture secrete AM. AM contributes to maternal systemic vasodilatation, the placental vessels are relaxed by AM in a dose-dependent manner and AM is expressed in the fetoplacental and umbilical vascular endothelium where basal production of AM contributes to low fetoplacental vascular resistances. Controversy exists over the status of circulating and placental AM in preeclampsia and of the relative contribution of AM to impaired fetoplacental circulation and fetal growth. Moreover, the uterus expresses AM mRNA and exogenous AM relaxes the myometrium in a dose-dependent manner; however, clinical studies have shown that AM does not decrease before the onset of parturition. Rather, AM secretion increases during spontaneous labor and in preterm delivery.
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Affiliation(s)
- Romolo Di Iorio
- Laboratory of Perinatal Medicine and Molecular Biology, Institute of Gynecology, Perinatology and Child Health, University La Sapienza, Viale Regina Elena, 324, I-00161, Rome, Italy.
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32
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Zudaire E, Cuttitta F, Martínez A. Regulation of pancreatic physiology by adrenomedullin and its binding protein. REGULATORY PEPTIDES 2003; 112:121-30. [PMID: 12667633 DOI: 10.1016/s0167-0115(03)00030-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Adrenomedullin (AM) is a 52 amino acid, multifunctional hormone. It is expressed in many tissues of the human body including the pancreas, where it is mainly localized to the periphery of the islets of Langerhans and specifically to the pancreatic polypeptide-expressing cells. The AM receptor, a complex formed by calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs), and the recently discovered AM-binding protein, complement factor H (fH), are expressed in the insulin-producing beta-cells. The colocalization of these key elements of the AM system in the endocrine portion of the pancreas implicates AM in the control of both normal and altered pancreatic physiologies. AM inhibits insulin secretion both in vitro (isolated rat islets) and in vivo (oral glucose tolerance test in rats) in a dose-dependent manner. The addition of fH to isolated rat islets produces a further reduction of insulin secretion in the presence of AM. Furthermore, AM is elevated in plasma from patients with pancreatic dysfunctions such as type 1 or type 2 diabetes and insulinoma. Using a diabetic model in rats, we have shown that AM increases circulating glucose levels whereas a blocking monoclonal antibody against AM has the opposite effect and improves postprandial recovery. Such experimental evidence implicates AM as a fundamental factor in maintaining insulin homeostasis and normoglycemia, and suggests the implication of AM as a possible causal agent in diabetes. Further investigation focused on the development of blocking agents for AM could result in new treatments for pancreatic AM-related disorders.
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Affiliation(s)
- E Zudaire
- Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 13N262, Bethesda, MD 20892, USA
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33
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Dobrzynski E, Montanari D, Agata J, Zhu J, Chao J, Chao L. Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 2002; 283:E1291-8. [PMID: 12424108 DOI: 10.1152/ajpendo.00147.2002] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Adrenomedullin (AM) is a potent vasodilating peptide and is involved in cardiovascular and renal disease. In the present study, we investigated the role of AM in cardiac and renal function in streptozotocin (STZ)-induced diabetic rats. A single tail-vein injection of adenoviral vectors harboring the human AM gene (Ad.CMV-AM) was administered to the rats 1-wk post-STZ treatment (65 mg/kg iv). Immunoreactive human AM was detected in the plasma and urine of STZ-diabetic rats treated with Ad.CMV-AM. Morphological and chemical examination showed that AM gene delivery significantly reduced glycogen accumulation within the hearts of STZ-diabetic rats. AM gene delivery improved cardiac function compared with STZ-diabetic rats injected with control virus, as observed by decreased left ventricular end-diastolic pressure, increased cardiac output, cardiac index, and heart rate. AM gene transfer significantly increased left ventricular long axis (11.69 +/- 0.46 vs. 10.31 +/- 0.70 mm, n = 10, P < 0.05) and rate of pressure rise and fall (+6,090.1 +/- 597.3 vs. +4,648.5 +/- 807.1 mmHg/s), (-4,902.6 +/- 644.2 vs. -3,915.5 +/- 805.8 mmHg/s, n = 11, P < 0.05). AM also significantly attenuated renal glycogen accumulation and tubular damage in STZ-diabetic rats as well as increased urinary cAMP and cGMP levels, along with increased cardiac cAMP and Akt phosphorylation. We also observed that delivery of the AM gene caused an increase in body weight along with phospho-Akt and membrane-bound GLUT4 levels in skeletal muscle. These results suggest that AM plays a protective role in hyperglycemia-induced glycogen accumulation and cardiac and renal dysfunction via Akt signal transduction pathways.
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Affiliation(s)
- Eric Dobrzynski
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Abstract
Adrenomedullin (AM) is a multiregulatory peptide which is expressed in a wide range of tissues. In the pancreas, AM was first found in mammals, including man, and its colocalization with the pancreatic polypeptide (PP) was established in islet F cells. In addition, three different AM receptors have been characterized in B-cells. AM has been also located in the pancreatic cells of other vertebrate classes. The frequency and distribution of AM cells vary between different animals; they can be found scattered among the exocrine tissue, in the islets, or in ductal epithelia. The colocalization of AM with other hormones presents different patterns, although in birds, as in mammals, it seems to colocalize only with PP. The best-determined pancreatic AM function is the inhibition of insulin secretion in B-cells, which seems to be linked to a recently discovered binding protein, factor H. In relation to this physiological role, clinical data show that AM is raised in some groups of both types I and II diabetic patients and AM might have triggered the disease in a subset of them. On the other hand, AM pancreatic cells are also involved in the response to septic shock by increasing AM circulating levels. A third putative function is the inhibition of amylase secretion by the exocrine pancreatic cells. AM has been found in embryonic mammalian pancreas from the earliest stages of the development, colocalizing with all pancreatic hormones, although in adults only coexpression with PP is kept. AM may play a role in the growth and morphogenesis of the pancreas.
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Affiliation(s)
- José López
- Department of Biology, Cell Biology Unit, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain.
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35
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MA CY, TANG CS, WANG HY. Increase of plasma adrenomedullin level in mesangial proliferative glomerulonephritis patients is correlated with tubulointerstitial lesion. ACTA ACUST UNITED AC 2002. [DOI: 10.1016/s1561-5413(09)60072-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Pío R, Martínez A, Cuttitta F. Cancer and diabetes: two pathological conditions in which adrenomedullin may be involved. Peptides 2001; 22:1719-29. [PMID: 11754957 DOI: 10.1016/s0196-9781(01)00530-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Adrenomedullin (AM) is a regulatory peptide involved in several physiological processes. Among them, AM has been implicated in the regulation of growth, both with mitogenic and antiproliferative activities on normal cells. AM is widely expressed during embryogenesis and may have a significant role in the proliferation and differentiation processes associated with development. AM is also expressed by cancer cell lines and tumors and has been implicated in the growth of malignant cells. Some additional activities associated with AM (antiapoptotic capabilities, angiogenic potential, and upregulation in hypoxic conditions), together with its wide distribution in cancer, suggest that AM may be an important factor in carcinogenesis. Besides its implication in growth, embryogenesis and tumor biology, AM is also involved in pancreatic regulation and diabetes. AM regulates insulin secretion and is overexpressed in the plasma of diabetic patients. Several findings indicate that AM may participate in the pathogenesis and/or clinical complications of this disease.
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Affiliation(s)
- R Pío
- Department of Biochemistry, School of Medicine, University of Navarra, 31080, Pamplona, Spain
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37
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Yoshida M, Yoshida H, Kitaichi K, Hiramatsu K, Kimura T, Ito Y, Kume H, Yamaki K, Suzuki R, Shibata E, Hasegawa T, Takagi K. Adrenomedullin and proadrenomedullin N-terminal 20 peptide induce histamine release from rat peritoneal mast cell. REGULATORY PEPTIDES 2001; 101:163-8. [PMID: 11495692 DOI: 10.1016/s0167-0115(01)00283-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Adrenomedullin (ADM)-induced histamine release from rat peritoneal mast cells was investigated. We compared the ability of full-length ADM to induce histamine release to the fragments ADM-(1-25) and ADM-(22-52), as well as proadrenomedullin N-terminal 20 peptide (PAMP). ADM (10(-8) to 10(-5) M) and PAMP (10(-8) to 10(-5) M) dose-dependently increased histamine release from peritoneal mast cell preparations. The effect of ADM-(1-25) was similar to ADM, whereas ADM-(22-52) did not show any effects. These data suggest the relative importance of the ADM C-terminal fragment, which contains a six-membered ring structure. Histamine release, induced by ADM, was significantly and dose-dependently inhibited by the addition of ADM-(22-52) (10(-5) M), Ca(2+) (0.5 to 2.0 mM), and benzalkonium chloride (3 to 7 microM), a selective inhibitor of Gi type G proteins. In contrast, PAMP (10(-5) M)-induced histamine release was not inhibited by Ca(2+). These results suggest that ADM induce histamine release via a putative ADM receptor in a manner sensitive to Gi-protein function and extracellular Ca(2+) concentration, and that PAMP might produce its effect by a different mechanism than ADM.
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Affiliation(s)
- M Yoshida
- Internal Medicine II, Nagoya University School of Medicine, 65 Tsuruma-Cho, Nagoya 466-8550, Showa, Japan
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Abstract
Adrenomedullin (AM) is a novel 52 amino acid peptide hormone, originally isolated from human pheochromocytoma. AM acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood pressure lowering properties. AM as a vasodilative molecule protects the vascular wall but its exact role is still uncertain. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis. Its plasma concentration in healthy conditions is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases in a parallel manner with the severity of the disease. It is assumed that this peptide plays an important role in physiological and pathological conditions compensating the effects of vasoconstrictive molecules. Investigations have proven that in diabetic angiopathies the levels and production of vasoconstrictive factors and AM are increased, while other relaxing substances such as nitric oxide (NO) are decreased. It is still uncertain whether the increased release of AM is a compensatory mechanism or a coincidental event. Although the precise role of AM in the pathogenesis of diabetic complications is still to be elucidated, the altered concentration of AM in diabetes could indicate a certain interaction between AM induction and vascular function. Hence, the induction of vascular AM can be a new target of therapeutic approach to diabetic complications.
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Affiliation(s)
- E Ruzicska
- 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
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40
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Anwaar I, Gottsäter A, Eriksson K, Jacobsson L, Lindgärde F, Mattiasson I. Increased plasma endothelin-1 and intraplatelet cyclic guanosine monophosphate in men with disturbed glucose metabolism. Diabetes Res Clin Pract 2000; 50:127-36. [PMID: 10960723 DOI: 10.1016/s0168-8227(00)00190-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Plasma endothelin-1, the nitric oxide (NO) mediator intraplatelet cyclic guanosine monophosphate (cGMP), the prostacyclin mediator cyclic adenosine monophosphate (cAMP) and the macrophage derived inflammatory mediator plasma neopterin were measured in men with Type 2 diabetes mellitus (n=91), impaired glucose tolerance (IGT; n=51), previously abnormal glucose tolerance (PAGT; n=20), and 34 healthy control men. Plasma endothelin-1was higher in men with Type 2 diabetes mellitus than in controls [4.1 (1.0-14.3) vs. 2.1 (0.2-8. 7) ng/l; P<0.001). Intraplatelet cGMP was higher in men with PAGT [0. 84 (0.57-2.76) pmol/10(9) platelets; P<0.05], IGT [0.85 (0.48-3.53); P<0.001] and Type 2 diabetes mellitus [0.90 (0.47-3.86); P<0.001] than in controls [0.70 (0.42-1.70]. No differences existed between groups concerning intraplatelet cAMP or plasma neopterin. Plasma endothelin-1 correlated with fasting plasma glucose (r=0.33; P<0.001) and HbA1(c) (r=0.29; P<0.001). In conclusion, elevated plasma endothelin-1 in Type 2 diabetes mellitus and its relationship to glucose and HbA1(c) suggest a putative role for endothelin-1 in diabetic endothelial cell damage. Increased cGMP indicating enhanced production/activity of NO suggests that factors other than reduced NO activity contribute to enhanced platelet aggregation in diabetes.
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Affiliation(s)
- I Anwaar
- Department of Medicine, University Hospital, S-205 02, Malmö, Sweden
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41
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Abstract
Since the discovery of adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing adrenomedullin far exceeding those that do not. 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. The data on circulating adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative adrenomedullin receptor clones and signal transduction pathways are described. 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. Finally, in Section V, we consider some unresolved issues and propose future areas for research.
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Affiliation(s)
- J P Hinson
- Department of Molecular and Cellular Biology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, United Kingdom.
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42
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Nagai Y, Yamashita H, Takamura T, Kobayashi KI. Does acute hyperinsulinaemia change plasma adrenomedullin concentration in healthy men? Diabet Med 2000; 17:249-50. [PMID: 10784234 DOI: 10.1046/j.1464-5491.2000.00231-3.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Hata T, Yanagihara T, Tanaka H, Yamashiro C, Kanenishi K. Maternal ophthalmic artery doppler velocimetry in type 1 diabetes during pregnancy. Hum Reprod 2000; 15:222-3. [PMID: 10611216 DOI: 10.1093/humrep/15.1.222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Our purpose was to evaluate whether maternal ophthalmic artery pulsatility index (PI) in normotensive pregnancies with type 1 diabetes is different from that in normal normotensive pregnancies. The ophthalmic artery in 15 normal normotensive pregnant women, and 13 normotensive pregnant women with type 1 diabetes was studied once with colour Doppler flow imaging and pulsed Doppler ultrasonography after 16 weeks gestation. The heart rate, mean arterial blood pressure, and ophthalmic artery PI were calculated in each group. The PI (1.94 +/- 0.45) in normotensive pregnant women with type 1 diabetes was significantly lower than that (2.73 +/- 0.32) in normal normotensive pregnant women (P < 0.0001). There was no significant difference in maternal heart rate or mean arterial blood pressure between the two groups. These results suggest that vascular resistance in the maternal orbital circulation is reduced in pregnancies with type 1 diabetes that are normotensive. The lower PI in pregnant women with type 1 diabetes should be interpreted as orbital vascular vasodilatation, indicating orbital hyperperfusion or hyperaemia.
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Affiliation(s)
- T Hata
- Department of Perinatology, Kagawa Medical University, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
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Martínez A, Elsasser TH, Bhathena SJ, Pío R, Buchanan TA, Macri CJ, Cuttitta F. Is adrenomedullin a causal agent in some cases of type 2 diabetes? Peptides 1999; 20:1471-8. [PMID: 10698123 DOI: 10.1016/s0196-9781(99)00158-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The study of two populations with a recent onset of type 2 diabetes showed that a subset of the patients had higher levels of adrenomedullin (AM) than the rest of the diabetics. In this subset, physiological elevations of AM might have triggered the disease in predisposed individuals. Diabetics showed higher levels of AM than healthy controls. In addition, glycemia was measured in diabetic rats after injection of saline, AM, or antiAM antibody. AM elevated glycemia, whereas the antibody reduced circulating glucose to normal. These results suggest that manipulation of AM levels could represent a new approach in the management of diabetes for the appropriate individuals.
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Affiliation(s)
- A Martínez
- Department of Cell and Cancer Biology, National Cancer Institute, Medicine Branch, Division of Clinical Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
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Hayashi M, Shimosawa T, Fujita T. Hyperglycemia increases vascular adrenomedullin expression. Biochem Biophys Res Commun 1999; 258:453-6. [PMID: 10329408 DOI: 10.1006/bbrc.1999.0664] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We have reported that plasma adrenomedullin (AM) in hyperglycemic patients was significantly increased compared with normal volunteers. In this report we examined the effects of hyperglycemia on AM expression in the vasculature, the main site of AM production. AM mRNA level in the aorta was higher in the diabetic rats than in the control rats. AM mRNA level and protein kinase C (PKC) activity in cultured vascular smooth muscle cells (VSMC) increased as the glucose concentration in the medium changed from 100mg/dl to 450mg/dl. PKC inhibitors blocked this increase of AM mRNA. Similar osmotic change with mannitol had no effect on AM expression. We conclude that (1) hyperglycemia increases vascular AM expression through PKC-dependent pathway, and (2) the elevated plasma AM in hyperglycemic patients originates from the glucose induced vascular AM expression. We propose the possible role of AM in the pathogenesis of diabetic vascular complications.
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Affiliation(s)
- M Hayashi
- School of Medicine, University of Tokyo, 3-28-6 Mejirodai, Bunkyo-ku, Tokyo, 112-8688, Japan.
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