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Martínez-Jiménez D, Hernández Del Rincón JP, Sabater-Molina M, Pérez-Martínez C, Torres C, Pérez-Cárceles MD, Luna A. Postmortem study of adrenomedullin and cortisol in femoral serum and pericardial fluid related to acute pulmonary edema. Int J Legal Med 2025; 139:353-359. [PMID: 39325159 PMCID: PMC11732926 DOI: 10.1007/s00414-024-03337-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
Currently, various tools aid in determining the cause of death and the circumstances surrounding it. Thanatochemistry is one such method that provides insights into the physiopathological mechanisms of death and the behavior of specific biomarkers in different body fluids postmortem. Certain biomarkers, characterized by their stability and specificity to vital tissues like the lungs, are associated with mechanisms contributing to death, such as acute pulmonary edema (APE). This study aims to analyze the behavior of midregional pro-adrenomedullin (MR-proADM) and cortisol levels, measured in pericardial fluid and femoral serum, in relation to the severity of APE, categorized according to specific criteria. Samples were collected from a total of 92 corpses (77 males, 15 females) with a mean age of 56.7 ± 15.2 years. The severity of APE associated with the deaths was classified into three groups: slight or absent (n = 7; 8.6%), medium or moderate (n = 16; 19.8%), and intense (n = 58;71.6%).The determination of MR-proADM and cortisol levels was conducted using ELISA kits and an Immunoassay Analyzer, respectively. Our results reveal a significant increase in MR-proADM concentration with the severity of APE. Furthermore, a correlation was established between cortisol and MR-proADM concentrations in both pericardial fluid and femoral serum samples. This indicates that the severity of APE influences the production of ADM, regardless of the specific underlying pathophysiological mechanisms. Cortisol values were also found to be higher in the intense APE group compared to the moderate group.This study contributes to our understanding of the relationship between MR-proADM and cortisol, and the severity of APE, shedding light on potential applications in postmortem investigations.
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Affiliation(s)
- Daniel Martínez-Jiménez
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
| | - Juan Pedro Hernández Del Rincón
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
- Institute of Legal Medicine and Forensic Sciences of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Maria Sabater-Molina
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain.
- Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
| | - Cristina Pérez-Martínez
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
| | - Carmen Torres
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
- Institute of Legal Medicine and Forensic Sciences of Murcia, Murcia, Spain
| | - María D Pérez-Cárceles
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
- Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Aurelio Luna
- Department of Legal and Forensic Medicine, University of Murcia, Campus Ciencias de la Salud Cmno Buenavista s/n 30120 El Palmar, Murcia, Spain
- Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Baldwin J, Burnier M, Ponte B, Ackermann D, Pruijm M, Vogt B, Bochud M. Association of mid-regional pro-adrenomedullin with office and 24-h ambulatory blood pressure in a Swiss general population sample. J Hypertens 2024; 42:2187-2195. [PMID: 39469923 PMCID: PMC11556881 DOI: 10.1097/hjh.0000000000003866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/20/2024] [Accepted: 08/23/2024] [Indexed: 10/30/2024]
Abstract
OBJECTIVE Adrenomedullin (ADM) is a potent vasodilator. The association between plasma ADM levels and blood pressure (BP) remains unclear. We assessed the association between mid-regional-pro-ADM (MR-proADM) and BP in a multicenter population- and family-based cohort. METHODS We used data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH). We included participants present at both baseline and 3-year follow-up (N = 843). We examined the association of baseline MR-proADM with baseline office and 24 h ambulatory BP as well as the 3-year change in office BP. In secondary analyses, we studied the association between baseline MR-proADM and 3-year changes in pulse wave velocity (PWV), renal resistive index (RRI) and augmentation index (AI). Mixed-effects linear regression models were used. RESULTS In cross-sectional analyses, MR-proADM was negatively associated with office, 24-h and daytime diastolic BP (DBP). MR-proADM was positively associated with nighttime systolic BP (SBP). In longitudinal analyses, baseline MR-proADM was associated with an increase in office SBP and pulse pressure (PP) over 3 years [β (95% CI): 8.2 (0.4, 15.9) and β (95% CI): 6.4 (0.3, 12.4), respectively] but not with changes in PWV, RRI and AI. CONCLUSIONS The cross-sectional negative association of MR-proADM with DBP is in line with known vasodilatory properties of ADM. The positive association between MR-proADM and nighttime SBP at baseline may reflect endothelial dysfunction believed to be part of the pathogenesis of nocturnal hypertension. The association of higher baseline MR-proADM levels with increased SBP and PP at 3-year follow-up suggests that ADM levels could be a marker of cardiovascular risk.
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Affiliation(s)
- Julia Baldwin
- Department of Epidemiology and Health Systems, Unisanté
| | | | - Belen Ponte
- Department of Nephrology, University Hospital of Geneva (HUG)
| | - Daniel Ackermann
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern
| | - Menno Pruijm
- Service of Nephrology and Hypertension, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
| | - Bruno Vogt
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern
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Chandler JC, Jafree DJ, Malik S, Pomeranz G, Ball M, Kolatsi-Joannou M, Piapi A, Mason WJ, Benest AV, Bates DO, Letunovska A, Al-Saadi R, Rabant M, Boyer O, Pritchard-Jones K, Winyard PJ, Mason AS, Woolf AS, Waters AM, Long DA. Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease. J Pathol 2024; 264:212-227. [PMID: 39177649 DOI: 10.1002/path.6339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/17/2024] [Accepted: 06/28/2024] [Indexed: 08/24/2024]
Abstract
WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jennifer C Chandler
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Daniyal J Jafree
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
- UCL MB/PhD Programme, Faculty of Medical Sciences, University College London, London, UK
| | - Saif Malik
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Gideon Pomeranz
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Mary Ball
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Maria Kolatsi-Joannou
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Alice Piapi
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
| | - William J Mason
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Andrew V Benest
- Endothelial Quiescence Group and Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - David O Bates
- Endothelial Quiescence Group and Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
- Pan-African Cancer Research Institute, University of Pretoria, Hatfield, South Africa
| | - Aleksandra Letunovska
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Reem Al-Saadi
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Marion Rabant
- Pathology department, Hôpital Universitaire Necker-Enfants Malades, Institut Imagine, Université Paris Cité, Paris, France
| | - Olivia Boyer
- APHP, Service de Néphrologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Institut Imagine, Université Paris Cité, Paris, France
| | - Kathy Pritchard-Jones
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
| | - Paul J Winyard
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
| | - Andrew S Mason
- Department of Biology and York Biomedical Research Institute, University of York, UK
| | - Adrian S Woolf
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Aoife M Waters
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
| | - David A Long
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London, UK
- UCL Centre for Kidney and Bladder Health, London, UK
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Harris NR, Bálint L, Dy DM, Nielsen NR, Méndez HG, Aghajanian A, Caron KM. The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries. Physiol Rev 2023; 103:391-432. [PMID: 35953269 PMCID: PMC9576179 DOI: 10.1152/physrev.00052.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/16/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022] Open
Abstract
The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.
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Affiliation(s)
- Natalie R Harris
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - László Bálint
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Danielle M Dy
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Natalie R Nielsen
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hernán G Méndez
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Amir Aghajanian
- Division of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kathleen M Caron
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Kiritani S, Ono Y, Takamatsu M, Oba A, Sato T, Ito H, Inoue Y, Takahashi Y. Diabetogenic liver metastasis from pancreatic cancer: a case report. Surg Case Rep 2022; 8:224. [PMID: 36576596 PMCID: PMC9797629 DOI: 10.1186/s40792-022-01582-8] [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: 11/04/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although new-onset diabetes has been described in up to 20% of patients with newly diagnosed pancreatic cancer, reports regarding new-onset diabetes associated with newly developed liver metastasis from pancreatic cancer are limited. CASE PRESENTATION A 60-year-old man was diagnosed with pancreatic tail cancer without impaired glycemic control. A curative-intent distal pancreatectomy with adjuvant S-1 chemotherapy was performed. Two years after surgery, a high HbA1c concentration and solitary liver metastasis were identified on follow-up examination. Two major chemotherapy regimens, gemcitabine/nab-paclitaxel and modified FOLFIRINOX, were sequentially administered to the patient; however, his carbohydrate 19-9 concentration continued to increase. Because the patient's glycemic control rapidly worsened in synchrony with the tumor growth, insulin therapy was initiated. Although the liver metastasis was refractory to chemotherapy, curative-intent left hepatectomy was performed because only one tumor remained. His impaired glycemic control improved immediately after surgery, and insulin therapy was terminated. When writing this report (2 years after hepatectomy), the patient was alive and recurrence-free. CONCLUSIONS New-onset diabetes appeared with the progression of metachronous liver metastasis from pancreatic cancer, without recurrence at any other site. The patient's diabetic state was improved by resection of the liver tumor, and liver metastasis itself was proven to have caused the glucometabolic disorder by increasing insulin resistance.
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Affiliation(s)
- Sho Kiritani
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yoshihiro Ono
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsushi Oba
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Takafumi Sato
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Hiromichi Ito
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yosuke Inoue
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Mid-Regional Pro-Adrenomedullin in Combination With Pediatric Early Warning Scores for Risk Stratification of Febrile Children Presenting to the Emergency Department: Secondary Analysis of a Nonprespecified United Kingdom Cohort Study. Pediatr Crit Care Med 2022; 23:980-989. [PMID: 36239515 PMCID: PMC9708078 DOI: 10.1097/pcc.0000000000003075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Current sepsis guidelines do not provide good risk stratification of subgroups in whom prompt IV antibiotics and fluid resuscitation might of benefit. We evaluated the utility of mid-regional pro-adrenomedullin (MR-proADM) in identification of patient subgroups at risk of requiring PICU or high-dependency unit (HDU) admission or fluid resuscitation. DESIGN Secondary, nonprespecified analysis of prospectively collected dataset. SETTING Pediatric Emergency Department in a United Kingdom tertiary center. PATIENTS Children less than 16 years old presenting with fever and clinical indication for venous blood sampling ( n = 1,183). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Primary outcome measures were PICU/HDU admission or administration of fluid resuscitation, with a secondary outcome of definite or probable bacterial infection. Biomarkers were measured on stored plasma samples and children phenotyped into bacterial and viral groups using a previously published algorithm. Of the 1,183 cases, 146 children (12.3%) required fluids, 48 (4.1%) were admitted to the PICU/HDU, and 244 (20.6%) had definite or probable bacterial infection. Area under the receiver operating characteristic (AUC) was used to assess performance. MR-proADM better predicted fluid resuscitation (AUC, 0.73; 95% CI, 0.67-0.78), than both procalcitonin (AUC, 0.65; 95% CI, 0.59-0.71) and Pediatric Early Warning Score (PEWS: AUC, 0.62; 95% CI, 0.56-0.67). PEWS alone showed good accuracy for PICU/HDU admission 0.83 (0.78-0.89). Patient subgroups with high MR-proADM (≥ 0.7 nmol/L) and high procalcitonin (≥ 0.5 ng/mL) had increased association with PICU/HDU admission, fluid resuscitation, and bacterial infection compared with subgroups with low MR-proADM (< 0.7 nmol/L). For children with procalcitonin less than 0.5 ng/mL, high MR-proADM improved stratification for fluid resuscitation only. CONCLUSIONS High MR-proADM and high procalcitonin were associated with increased likelihood of subsequent disease progression. Incorporating MR-proADM into clinical risk stratification may be useful in clinician decision-making regarding initiation of IV antibiotics, fluid resuscitation, and escalation to PICU/HDU admission.
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Chin CG, Elimam AM, Lin FJ, Chen YC, Lin YK, Lu YY, Higa S, Chen SA, Hsieh MH, Chen YJ. Effects of Adrenomedullin on Atrial Electrophysiology and Pulmonary Vein Arrhythmogenesis. Int J Mol Sci 2022; 23:ijms232214064. [PMID: 36430541 PMCID: PMC9696567 DOI: 10.3390/ijms232214064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/16/2022] Open
Abstract
Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an increased risk of atrial fibrillation (AF), but the effects of adrenomedullin on atrial arrhythmogenesis remain unclear. This study investigated whether adrenomedullin modulates the electrophysiology of the atria (AF substrate) or pulmonary vein (PV; AF trigger) arrhythmogenesis. Conventional microelectrode or whole-cell patch clamps were used to study the effects of adrenomedullin (10, 30, and 100 pg/mL) on the electrical activity, mechanical response, and ionic currents of isolated rabbit PV and sinoatrial node tissue preparations and single PV cardiomyocytes. At 30 and 100 pg/mL, adrenomedullin significantly reduced the spontaneous beating rate of the PVs from 2.0 ± 0.4 to 1.3 ± 0.5 and 1.1 ± 0.5 Hz (reductions of 32.9% ± 7.1% and 44.9 ± 8.4%), respectively, and reduced PV diastolic tension by 12.8% ± 4.1% and 14.5% ± 4.1%, respectively. By contrast, adrenomedullin did not affect sinoatrial node beating. In the presence of L-NAME (a nitric oxide synthesis inhibitor, 100 μM), adrenomedullin (30 pg/mL) did not affect the spontaneous beating rate or diastolic tension of the PVs. In the single-cell experiments, adrenomedullin (30 pg/mL) significantly reduced the L-type calcium current (ICa-L) and reverse-mode current of the sodium-calcium exchanger (NCX). Adrenomedullin reduces spontaneous PV activity and PV diastolic tension by reducing ICa-L and NCX current and thus may be useful for treating atrial tachyarrhythmia.
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Affiliation(s)
- Chye-Gen Chin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei 11696, Taiwan
| | - Ahmed Moustafa Elimam
- Division of Cardiovascular Medicine, Department of Internal Medicine, Mansoura International Hospital, Mansoura 35511, Egypt
| | - Fong-Jhih Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yung-Kuo Lin
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei 11696, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
| | - Yen-Yu Lu
- Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 901-2131, Japan
| | - Shih-Ann Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Ming-Hsiung Hsieh
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei 11696, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
- Correspondence: (M.-H.H.); (Y.-J.C.); Tel.: +886-0970746502 (Y.-J.C.); Fax: +886-2-2933-9378 (Y.-J.C.)
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei 11696, Taiwan
- Correspondence: (M.-H.H.); (Y.-J.C.); Tel.: +886-0970746502 (Y.-J.C.); Fax: +886-2-2933-9378 (Y.-J.C.)
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Hosoda H, Nakamura T, Yoshihara F. Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure. Biomolecules 2022; 12:biom12091281. [PMID: 36139120 PMCID: PMC9496228 DOI: 10.3390/biom12091281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 12/02/2022] Open
Abstract
Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous injection of mercury chloride (RD-Ag) and the other by completely blocking bilateral renal blood flow (RD-Bl). Sixty minutes after starting intravenous AM infusion, AM levels in RD-Ag, RD-Bl, and rats with normal renal function (NF) were still increased slightly; however, plasma AM levels in RD-Ag rats were approximately three times as high as in RD-Bl and NF rats. Plasma AM disappearance after the end of treatment was similar among the three groups. Pharmacokinetic analysis revealed that elevated plasma AM in RD-Ag rats may be caused by a reduced volume of distribution. The adrenomedullin functional receptor is composed of heterodimers, including GPCR, CLR (calcitonin receptor-like receptor, CALCRL), and the single transmembrane proteins, RAMP2 or RAMP3 (receptor activity modifying protein). Calcrl expression was downregulated in the lungs and kidneys of RD-Ag rats. Furthermore, the plasma concentration of exogenous AM was elevated in mice deficient in vascular endothelium-specific Ramp2. These results suggest that decreased plasma AM clearance in RD-Ag is not due to impaired renal excretion but to a decreased volume of distribution caused by a reduction in adrenomedullin receptors.
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Affiliation(s)
- Hiroshi Hosoda
- Department of Hypertension and Nephrology, National Cerebral and Cardiovascular Center Hospital, 6-1 Kishibe-Shimmachi, Suita 564-8565, Osaka, Japan
- Department of Molecular Pathophysiology, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Nagano, Japan
- Correspondence:
| | - Tsutomu Nakamura
- Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan
| | - Fumiki Yoshihara
- Department of Hypertension and Nephrology, National Cerebral and Cardiovascular Center Hospital, 6-1 Kishibe-Shimmachi, Suita 564-8565, Osaka, Japan
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Omran F, Kyrou I, Osman F, Lim VG, Randeva HS, Chatha K. Cardiovascular Biomarkers: Lessons of the Past and Prospects for the Future. Int J Mol Sci 2022; 23:5680. [PMID: 35628490 PMCID: PMC9143441 DOI: 10.3390/ijms23105680] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are a major healthcare burden on the population worldwide. Early detection of this disease is important in prevention and treatment to minimise morbidity and mortality. Biomarkers are a critical tool to either diagnose, screen, or provide prognostic information for pathological conditions. This review discusses the historical cardiac biomarkers used to detect these conditions, discussing their application and their limitations. Identification of new biomarkers have since replaced these and are now in use in routine clinical practice, but still do not detect all disease. Future cardiac biomarkers are showing promise in early studies, but further studies are required to show their value in improving detection of CVD above the current biomarkers. Additionally, the analytical platforms that would allow them to be adopted in healthcare are yet to be established. There is also the need to identify whether these biomarkers can be used for diagnostic, prognostic, or screening purposes, which will impact their implementation in routine clinical practice.
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Affiliation(s)
- Farah Omran
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Faizel Osman
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ven Gee Lim
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Harpal Singh Randeva
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX, UK
| | - Kamaljit Chatha
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK; (F.O.); (I.K.); (F.O.); (V.G.L.); (H.S.R.)
- Biochemistry and Immunology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
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10
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Mid-Regional Proadrenomedullin as a New Biomarker of Kidney and Cardiovascular Diseases-Is It the Future? J Clin Med 2021; 10:jcm10030524. [PMID: 33540505 PMCID: PMC7867137 DOI: 10.3390/jcm10030524] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/22/2021] [Accepted: 01/27/2021] [Indexed: 01/19/2023] Open
Abstract
The increasing prevalence of cardiovascular disease and concomitant chronic kidney disease among the aging populations is responsible for considerable growth of mortality. Additionally, frequent, prolonged hospitalizations and long-term treatment generates progressive decline in bodily functions as well as substantial public health and economic burden. Accessibility to easy, non-invasive prognostic markers able to detect patients at risk of cardiovascular events may improve effective therapy and mitigate disease progression. Moreover, an early diagnosis allows time for implementation of prophylactic and educational programs that may result in decreased morbidity, improved quality of life and reduced public health expenditure. One of the promising candidates for a novel cardiovascular biomarker is mid-regional proadrenomedullin, a derivative of adrenomedullin. Adrenomedullin is a peptide hormone known for its vasodilatory, antioxidant, antiapoptotic and antifibrotic effects. A remarkable advantage of mid-regional proadrenomedullin is its longer half-life which is a prerequisite for plasma measurements. These review aims to discuss the importance of mid-regional proadrenomedullin with reference to its usefulness as a biomarker of increased cardiovascular risk and kidney disease progression.
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11
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Koyama T, Kuriyama N, Suzuki Y, Saito S, Tanaka R, Iwao M, Tanaka M, Maki T, Itoh H, Ihara M, Shindo T, Uehara R. Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study. Sci Rep 2021; 11:305. [PMID: 33431996 PMCID: PMC7801498 DOI: 10.1038/s41598-020-79525-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.
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Affiliation(s)
- Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Nagato Kuriyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yosuke Suzuki
- Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Japan.,Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Satoshi Saito
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Ryota Tanaka
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Motoshi Iwao
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Takakuni Maki
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroki Itoh
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Ritei Uehara
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
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12
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Vázquez R, Riveiro ME, Berenguer-Daizé C, O'Kane A, Gormley J, Touzelet O, Rezai K, Bekradda M, Ouafik L. Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy. Front Oncol 2021; 10:589218. [PMID: 33489885 PMCID: PMC7815935 DOI: 10.3389/fonc.2020.589218] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/02/2020] [Indexed: 12/18/2022] Open
Abstract
The development, maintenance and metastasis of solid tumors are highly dependent on the formation of blood and lymphatic vessels from pre-existing ones through a series of processes that are respectively known as angiogenesis and lymphangiogenesis. Both are mediated by specific growth-stimulating molecules, such as the vascular endothelial growth factor (VEGF) and adrenomedullin (AM), secreted by diverse cell types which involve not only the cancerogenic ones, but also those constituting the tumor stroma (i.e., macrophages, pericytes, fibroblasts, and endothelial cells). In this sense, anti-angiogenic therapy represents a clinically-validated strategy in oncology. Current therapeutic approaches are mainly based on VEGF-targeting agents, which, unfortunately, are usually limited by toxicity and/or tumor-acquired resistance. AM is a ubiquitous peptide hormone mainly secreted in the endothelium with an important involvement in blood vessel development and cardiovascular homeostasis. In this review, we will introduce the state-of-the-art in terms of AM physiology, while putting a special focus on its pro-tumorigenic role, and discuss its potential as a therapeutic target in oncology. A large amount of research has evidenced AM overexpression in a vast majority of solid tumors and a correlation between AM levels and disease stage, progression and/or vascular density has been observed. The analysis presented here indicates that the involvement of AM in the pathogenesis of cancer arises from: 1) direct promotion of cell proliferation and survival; 2) increased vascularization and the subsequent supply of nutrients and oxygen to the tumor; 3) and/or alteration of the cell phenotype into a more aggressive one. Furthermore, we have performed a deep scrutiny of the pathophysiological prominence of each of the AM receptors (AM1 and AM2) in different cancers, highlighting their differential locations and functions, as well as regulatory mechanisms. From the therapeutic point of view, we summarize here an exhaustive series of preclinical studies showing a reduction of tumor angiogenesis, metastasis and growth following treatment with AM-neutralizing antibodies, AM receptor antagonists, or AM receptor interference. Anti-AM therapy is a promising strategy to be explored in oncology, not only as an anti-angiogenic alternative in the context of acquired resistance to VEGF treatment, but also as a potential anti-metastatic approach.
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Affiliation(s)
- Ramiro Vázquez
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France.,Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Maria E Riveiro
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France
| | | | - Anthony O'Kane
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Julie Gormley
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Olivier Touzelet
- Discovery and Scientific Affairs Department, Fusion Antibodies plc., Belfast, United Kingdom
| | - Keyvan Rezai
- Department of Radio-Pharmacology, Institute Curie-René Huguenin Hospital, Saint-Cloud, France
| | - Mohamed Bekradda
- Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France
| | - L'Houcine Ouafik
- Aix Marseille University, CNRS, INP, Institute of NeuroPhysiopathology, Marseille, France.,APHM, CHU Nord, Service de Transfert d'Oncologie Biologique, Marseille, France
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13
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Edfors R, Lindhagen L, Spaak J, Evans M, Andell P, Baron T, Mörtberg J, Rezeli M, Salzinger B, Lundman P, Szummer K, Tornvall P, Wallén HN, Jacobson SH, Kahan T, Marko-Varga G, Erlinge D, James S, Lindahl B, Jernberg T. Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction. J Intern Med 2020; 288:581-592. [PMID: 32638487 DOI: 10.1111/joim.13116] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 04/30/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.
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Affiliation(s)
- R Edfors
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.,Bayer AB, Solna, Sweden
| | - L Lindhagen
- Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - J Spaak
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - M Evans
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - P Andell
- Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden
| | - T Baron
- Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - J Mörtberg
- Department of Clinical Sciences, Division of Renal Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - M Rezeli
- Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - B Salzinger
- Department of Clinical Sciences, Division of Renal Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - P Lundman
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - K Szummer
- Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden
| | - P Tornvall
- Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden
| | - H N Wallén
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - S H Jacobson
- Department of Clinical Sciences, Division of Renal Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - T Kahan
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | - G Marko-Varga
- Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - D Erlinge
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
| | - S James
- Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - B Lindahl
- Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - T Jernberg
- From the, Department of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
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14
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Midregional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers. J Hypertens 2020; 37:590-595. [PMID: 30540625 DOI: 10.1097/hjh.0000000000001893] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up. METHODS We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmö Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally. RESULTS At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ± standard error, P value) higher SBP (0.956 ± 0.319 mmHg, P = 0.003), BMI (0.912 ± 0.061 kg/m, P = 1.42 × 10), waist (2.28 ± 0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ± 0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ± 0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ± 0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ± 0.051 kg/m, P = 0.047) and waist (0.600 ± 0.144 cm, P = 3.1 × 10). CONCLUSION Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM.
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15
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Yan H, Jin S, Liang L, Du J, Aithal GP, Li L. Pro-adrenomedullin in acute decompensation of liver cirrhosis: relationship with acute-on-chronic liver failure and short-term survival. Scand J Gastroenterol 2020; 55:606-614. [PMID: 32476510 DOI: 10.1080/00365521.2020.1764616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background and aim: Acute-on-chronic liver failure (ACLF) is characterized by the presence of acute decompensation (AD) of cirrhosis, organ failures, and high short-term mortality rates. In present study, we explored whether Pro-adrenomedullin (Pro-ADM), a biomarker of sepsis, is a potential marker of outcome in patients admitted for AD or ACLF and whether it might be of additional value to conventional prognostic scoring systems in these patients.Methods: 332 consecutive patients with AD of cirrhosis were prospectively enrolled. Pro-ADM was measured for all patients at baseline. Cox regression analysis was used to evaluate the impact of pro-ADM on short-term survival and developing ACLF during hospital stay.Results: Serum pro-ADM levels were significantly high in non-survivors (p < .001) and showed significant correlation with ALT (r = 0.181, p = .001), INR (r = 0.144, p = .009), TB (r = 0.368, p < .001), Creatinine (r = 0.145, p = .004), MELD score (r = 0.334, p = <.001) and CLI-C OF score (r = 0.375, p= <.001). Serum pro-ADM at admission was shown to be a predictor of 28-day mortality independently of MELD and CLIF-C OF scores. Prognostic models incorporating pro-ADM achieved high C index for predicting 28-day mortality in AD patients of cirrhosis. Moreover, baseline pro-ADM was found to be predictive of ACLF development during hospital stay.Conclusions: Serum pro-ADM levels correlate with multiorgan failure and are independently associated with short-term survival and ACLF development in patients admitted for AD or ACLF.
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Affiliation(s)
- Huadong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Department of Hepatology, Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwamei Hospital, Ningbo No.2 Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Susu Jin
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Lili Liang
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Jingyuan Du
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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16
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Identification of ADPKD-Related Genes and Pathways in Cells Overexpressing PKD2. Genes (Basel) 2020; 11:genes11020122. [PMID: 31979107 PMCID: PMC7074416 DOI: 10.3390/genes11020122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 11/17/2022] Open
Abstract
Consistent with the gene dosage effect hypothesis, renal cysts can arise in transgenic murine models overexpressing either PKD1 or PKD2, which are causal genes for autosomal dominant polycystic kidney disease (ADPKD). To determine whether PKD gene overexpression is a universal mechanism driving cystogenesis or is merely restricted to rodents, other animal models are required. Previously, we failed to observe any renal cysts in a transgenic porcine model of PKD2 overexpression partially due to epigenetic silencing of the transgene. Thus, to explore the feasibility of porcine models and identify potential genes/pathways affected in ADPKD, LLC-PK1 cells with high PKD2 expression were generated. mRNA sequencing (RNA-seq) was performed, and MYC, IER3, and ADM were found to be upregulated genes common to the different PKD2 overexpression cell models. MYC is a well-characterized factor contributing to cystogenesis, and ADM is a biomarker for chronic kidney disease. Thus, these genes might be indicators of disease progression. Additionally, some ADPKD-associated pathways, e.g., the mitogen-activated protein kinase (MAPK) pathway, were enriched in the cells. Moreover, gene ontology (GO) analysis demonstrated that proliferation, apoptosis, and cell cycle regulation, which are hallmarks of ADPKD, were altered. Therefore, our experiment identified some biomarkers or indicators of ADPKD, indicating that high PKD2 expression would likely drive cystogenesis in future porcine models.
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17
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Manor O, Zubair N, Conomos MP, Xu X, Rohwer JE, Krafft CE, Lovejoy JC, Magis AT. A Multi-omic Association Study of Trimethylamine N-Oxide. Cell Rep 2020; 24:935-946. [PMID: 30044989 DOI: 10.1016/j.celrep.2018.06.096] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/17/2018] [Accepted: 06/22/2018] [Indexed: 01/16/2023] Open
Abstract
Trimethylamine N-oxide (TMAO) is a circulating metabolite that has been implicated in the development of atherosclerosis and cardiovascular disease (CVD). In this paper, we identify blood markers, metabolites, proteins, gut microbiota patterns, and diets that are significantly associated with levels of plasma TMAO. We find that kidney markers are strongly associated with TMAO and identify CVD-related proteins that are positively correlated with TMAO. We show that metabolites derived by the gut microbiota are strongly correlated with TMAO and that the magnitude of this correlation varies with kidney function. Moreover, we identify diet-associated patterns in the microbiome that are correlated with TMAO. These findings suggest that both the process of TMAO accumulation and the mechanism by which TMAO promotes atherosclerosis are a complex interplay between diet and the microbiome on one hand and other system-level factors such as circulating proteins, metabolites, and kidney function.
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Affiliation(s)
| | | | | | | | | | | | - Jennifer C Lovejoy
- Arivale, Inc., Seattle, WA 98104, USA; Institute for Systems Biology, Seattle, WA 98109, USA
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18
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Iring A, Jin YJ, Albarrán-Juárez J, Siragusa M, Wang S, Dancs PT, Nakayama A, Tonack S, Chen M, Künne C, Sokol AM, Günther S, Martínez A, Fleming I, Wettschureck N, Graumann J, Weinstein LS, Offermanns S. Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. J Clin Invest 2019; 129:2775-2791. [PMID: 31205027 DOI: 10.1172/jci123825] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 05/01/2019] [Indexed: 12/22/2022] Open
Abstract
Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.
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Affiliation(s)
- Andras Iring
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Young-June Jin
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Julián Albarrán-Juárez
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Mauro Siragusa
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany
| | - ShengPeng Wang
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Yanta District, Xi'an, China
| | - Péter T Dancs
- Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary
| | - Akiko Nakayama
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Sarah Tonack
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Min Chen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | | | - Anna M Sokol
- Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | | | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany
| | - Nina Wettschureck
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,German Centre for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany.,Centre for Molecular Medicine, Medical Faculty, Goethe University, Frankfurt am Main, Germany
| | - Johannes Graumann
- German Centre for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany.,Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,German Centre for Cardiovascular Research (DZHK), Rhine-Main site, Frankfurt and Bad Nauheim, Germany.,Centre for Molecular Medicine, Medical Faculty, Goethe University, Frankfurt am Main, Germany
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19
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Simonyte S, Kuciene R, Dulskiene V, Lesauskaite V. Associations of the adrenomedullin gene polymorphism with prehypertension and hypertension in Lithuanian children and adolescents: a cross-sectional study. Sci Rep 2019; 9:6807. [PMID: 31048758 PMCID: PMC6497928 DOI: 10.1038/s41598-019-43287-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 04/04/2019] [Indexed: 11/09/2022] Open
Abstract
The aim of this study was to evaluate the association of ADM genetic variant and HBP among Lithuanian adolescents aged 12-15 years. This is a cross-sectional study of a randomly selected sample of 675 12-15-years-old schoolchildren who were surveyed during November 2010 to April 2012 in the baseline survey. Single-nucleotide polymorphism (SNP) of ADM gene (rs7129220) was evaluated using real-time PCR. Logistic regression analyses were used to test the associations of ADM (rs7129220) polymorphism with HBP under four inheritance models based on the Akaike Information Criterion (AIC) and to calculate the odds ratios. In the multivariate analysis, boys carrying ADM AG genotype (vs. carriers of ADM GG genotype), ADM AG + AA genotype (vs. carriers of ADM GG genotype) and ADM AG genotype (vs. carriers of ADM GG + AA genotype) had higher odds of having hypertension in codominant, dominant, and overdominant inheritance models. Girls with ADM AG + AA had increased odds of prehypertension compared to girls with the ADM GG genotype carriers in dominant inheritance model. Significant associations were observed in additive models separately for boys (hypertension) and girls (prehypertension). Our results indicate that ADM gene polymorphism was significantly associated with higher odds of HBP in Lithuanian adolescents aged 12-15 years.
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Affiliation(s)
- Sandrita Simonyte
- Institute of Cardiology of the Medical Academy, Lithuanian University of Health Sciences, Sukileliu 15, LT-50161, Kaunas, Lithuania.
| | - Renata Kuciene
- Institute of Cardiology of the Medical Academy, Lithuanian University of Health Sciences, Sukileliu 15, LT-50161, Kaunas, Lithuania
| | - Virginija Dulskiene
- Institute of Cardiology of the Medical Academy, Lithuanian University of Health Sciences, Sukileliu 15, LT-50161, Kaunas, Lithuania
| | - Vaiva Lesauskaite
- Institute of Cardiology of the Medical Academy, Lithuanian University of Health Sciences, Sukileliu 15, LT-50161, Kaunas, Lithuania
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20
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Ozcelik F, Pence HH, Ozturkeri HY, Sertoğlu E. Adrenomedullin as a Protein with Multifunctional Behavior and Effects in Various Organs and Tissues. ACTA ACUST UNITED AC 2019. [DOI: 10.14302/issn.2641-9181.ijnr-19-2771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In literature, it has been reported that adrenomedullin, which is generally thought to have vasodilator, natriuretic and diuretic effects, is synthesized in almost all body, especially CNS, vascular muscles and endothelium, heart, liver, lung, kidney, gastric mocosa, intestinal endothelium and various blood cells. It has been found that the possible effects of adrenomedullin can be demonstrated directly or indirectly by means of active mediators, neuropeptides, enzymes and hormones. It is also suggested that it regulates the endocrine system by affecting the hypothalamic-pituitary axis. It increases in heart failure, acute coronary syndromes, hypertensive conditions, cerebrovascular accessory, chronic renal failure and periodontitis and decreases in peptic ulcer and intestinal diseases. However, it is still not clear whether increase/decrease in adrenomedullin level is a cause of a disease or is a result of damage due to an illness. This peptide, which could be thought to multifunctional, should be considered as a molecule with genetic coding that may have different effects on different tissues and conditions. For all these reasons, we aimed to review the multifonctional behavior of adrenomedullin in the light of the current literature to pioneer new hypotheses and discuss possible mechanisms.
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Affiliation(s)
- Fatih Ozcelik
- University of Health Sciences, Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
| | - Halime Hanim Pence
- University of Health Sciences, Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
| | - Hilal Yalcin Ozturkeri
- University of Health Sciences, Haydarpasa Numune Training Hospital, Department of Medical Biochemistry, Istanbul, Turkey
| | - Erdim Sertoğlu
- University of Health Sciences, Gulhane Faculty of Medicine, Department of Medical Biochemistry, Istanbul, Turkey
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21
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Tsuruda T, Kato J, Kuwasako K, Kitamura K. Adrenomedullin: Continuing to explore cardioprotection. Peptides 2019; 111:47-54. [PMID: 29577955 DOI: 10.1016/j.peptides.2018.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/15/2018] [Accepted: 03/19/2018] [Indexed: 10/17/2022]
Abstract
Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or -independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.
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Affiliation(s)
- Toshihiro Tsuruda
- Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
| | - Johji Kato
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Japan
| | - Kenji Kuwasako
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Japan
| | - Kazuo Kitamura
- Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
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22
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Natural and synthetic peptides in the cardiovascular diseases: An update on diagnostic and therapeutic potentials. Arch Biochem Biophys 2018; 662:15-32. [PMID: 30481494 DOI: 10.1016/j.abb.2018.11.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/31/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
Abstract
Several peptides play an important role in physiological and pathological conditions into the cardiovascular system. In addition to well-known vasoactive agents such as angiotensin II, endothelin, serotonin or natriuretic peptides, the vasoconstrictor Urotensin-II (Uro-II) and the vasodilators Urocortins (UCNs) and Adrenomedullin (AM) have been implicated in the control of vascular tone and blood pressure as well as in cardiovascular disease states including congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Therefore these peptides, together with their receptors, become important therapeutic targets in cardiovascular diseases (CVDs). Circulating levels of these agents in the blood are markedly modified in patients with specific CVDs compared with those in healthy patients, becoming also potential biomarkers for these pathologies. This review will provide an overview of current knowledge about the physiological roles of Uro-II, UCN and AM in the cardiovascular system and their implications in cardiovascular diseases. It will further focus on the structural modifications carried out on original peptide sequences in the search of analogues with improved physiochemical properties as well as in the delivery methods. Finally, we have overviewed the possible application of these peptides and/or their precursors as biomarkers of CVDs.
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23
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Lyngbakken MN, Myhre PL, Røsjø H, Omland T. Novel biomarkers of cardiovascular disease: Applications in clinical practice. Crit Rev Clin Lab Sci 2018; 56:33-60. [DOI: 10.1080/10408363.2018.1525335] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Magnus Nakrem Lyngbakken
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Peder Langeland Myhre
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Helge Røsjø
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Torbjørn Omland
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Center for Heart Failure Research, University of Oslo, Oslo, Norway
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24
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Saad NS, Elnakish MT, Ahmed AAE, Janssen PML. Protein Kinase A as a Promising Target for Heart Failure Drug Development. Arch Med Res 2018; 49:530-537. [PMID: 30642654 PMCID: PMC6451668 DOI: 10.1016/j.arcmed.2018.12.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 12/13/2018] [Indexed: 12/24/2022]
Abstract
Heart failure (HF) is a clinical syndrome characterized by impaired ability of the heart to fill or eject blood. HF is rather prevalent and it represents the foremost reason of hospitalization in the United States. The costs linked to HF overrun those of all other causes of disabilities, and death in the United States and all over the developed as well as the developing countries which amplify the supreme significance of its prevention. Protein kinase (PK) A plays multiple roles in heart functions including, contraction, metabolism, ion fluxes, and gene transcription. Altered PKA activity is likely to cause the progression to cardiomyopathy and HF. Thus, this review is intended to focus on the roles of PKA and PKA-mediated signal transduction in the healthy heart as well as during the development of HF. Furthermore, the impact of cardiac PKA inhibition/activation will be highlighted to identify PKA as a potential target for the HF drug development.
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Affiliation(s)
- Nancy S Saad
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Mohammad T Elnakish
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Amany A E Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Paul M L Janssen
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
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25
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Vanholder R, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, Dedeyn P, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Massy Z, Rodriguez M, Stegmayr B, Stenvinkel P, Wratten M. Uremic Toxicity: Present State of the Art. Int J Artif Organs 2018. [DOI: 10.1177/039139880102401004] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.
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Affiliation(s)
- R. Vanholder
- The Nephrology Section, Department of Internal Medicine, University Hospital, Gent - Belgium
| | - A. Argilés
- Institute of Human Genetics, IGH-CNRS UPR 1142, Montpellier - France
| | | | - P. Brunet
- Nephrology, Internal Medicine, Ste Marguerite Hospital, Marseille - France
| | - W. Clark
- Baxter Healthcare Corporation, Lessines - Belgium
| | - G. Cohen
- Division of Nephrology, Department of Medicine, University of Vienna, Vienna - Austria
| | - P.P. Dedeyn
- Department of Neurology, Middelheim Hospital, Laboratory of Neurochemistry and Behaviour, University of Antwerp - Belgium
| | - R. Deppisch
- Gambro Corporate Research, Hechingen - Germany
| | | | - T. Henle
- Institute of Food Chemistry, Technical University, Dresden - Germany
| | - A. Jörres
- Nephrology and Medical Intensive Care, UK Charité, Campus Virchow-Klinikum, Medical Faculty of Humboldt-University, Berlin - Germany
| | - Z.A. Massy
- Division of Nephrology, CH-Beauvais, and INSERM Unit 507, Necker Hospital, Paris - France
| | - M. Rodriguez
- University Hospital Reina Sofia, Research Institute, Cordoba - Spain
| | - B. Stegmayr
- Norrlands University Hospital, Medical Clinic, Umea - Sweden
| | - P. Stenvinkel
- Nephrology Department, University Hospital, Huddinge - Sweden
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26
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Nishino T, Yoshida T, Goto M, Inoue S, Minato T, Fujiwara S, Yamamoto Y, Furukita Y, Yuasa Y, Yamai H, Takechi H, Toba H, Takizawa H, Yoshida M, Seike J, Miyoshi T, Tangoku A. The effects of the herbal medicine Daikenchuto (TJ-100) after esophageal cancer resection, open-label, randomized controlled trial. Esophagus 2018; 15:75-82. [PMID: 29892933 PMCID: PMC5884909 DOI: 10.1007/s10388-017-0601-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 12/11/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. METHODS Forty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. RESULTS We examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups. CONCLUSIONS TJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.
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Affiliation(s)
- Takeshi Nishino
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
| | - Takahiro Yoshida
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Masakazu Goto
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Seiya Inoue
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takuya Minato
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Satoshi Fujiwara
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yota Yamamoto
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yoshihito Furukita
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasuhiro Yuasa
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiromichi Yamai
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hirokazu Takechi
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiroaki Toba
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiromitsu Takizawa
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuteru Yoshida
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Junichi Seike
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takanori Miyoshi
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Akira Tangoku
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
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27
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Weber J, Sachse J, Bergmann S, Sparwaßer A, Struck J, Bergmann A. Sandwich Immunoassay for Bioactive Plasma Adrenomedullin. ACTA ACUST UNITED AC 2017; 2:222-233. [DOI: 10.1373/jalm.2017.023655] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 05/05/2017] [Indexed: 11/06/2022]
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28
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Xian X, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Tanaka M, Koyama T, Kawate H, Yang L, Liu T, Imai A, Zhai L, Hirabayashi K, Dai K, Tanimura K, Liu T, Cui N, Igarashi K, Yamauchi A, Shindo T. Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells. Endocrinology 2017; 158:1359-1372. [PMID: 28324104 DOI: 10.1210/en.2016-1531] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 01/24/2017] [Indexed: 12/31/2022]
Abstract
Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after coronary intervention. We previously described the essential angiogenic function of the adrenomedullin (AM)-receptor activity-modifying protein (RAMP) 2 system. In the present study, we assessed the vasoprotective actions of the endogenous AM-RAMP2 system using a wire-induced vascular injury model. We found that neointima formation and vascular smooth muscle cell proliferation were enhanced in RAMP2+/- male mice. The injured vessels from RAMP2+/- mice showed greater macrophage infiltration, inflammatory cytokine expression, and oxidative stress than vessels from wild-type mice and less re-endothelialization. After endothelial cell-specific RAMP2 deletion in drug-inducible endothelial cell-specific RAMP2-/- (DI-E-RAMP2-/-) male mice, we observed markedly greater neointima formation than in control mice. In addition, neointima formation after vessel injury was enhanced in mice receiving bone marrow transplants from RAMP2+/- or DI-E-RAMP2-/- mice, indicating that bone marrow-derived cells contributed to the enhanced neointima formation. Finally, we found that the AM-RAMP2 system augmented proliferation and migration of endothelial progenitor cells. These results demonstrate that the AM-RAMP2 system exerts crucial vasoprotective effects after vascular injury and could be a therapeutic target for the treatment of vascular diseases.
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Affiliation(s)
- Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
- Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang 050017, China
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Teruhide Koyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Lei Yang
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 0050017, China
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Kun Dai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Keiya Tanimura
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Teng Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
| | | | | | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan
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29
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Schönauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci 2017; 23:472-485. [DOI: 10.1002/psc.2953] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 11/24/2016] [Accepted: 11/28/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Ria Schönauer
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
| | - Sylvia Els-Heindl
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
| | - Annette G. Beck-Sickinger
- Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry; Leipzig University; Brüderstraße 34 04103 Leipzig Germany
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30
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Bastos P, Trindade F, da Costa J, Ferreira R, Vitorino R. Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era. Med Res Rev 2017; 38:101-146. [PMID: 28094448 PMCID: PMC7168463 DOI: 10.1002/med.21435] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 11/04/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
Abstract
Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide-based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions.
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Affiliation(s)
- Paulo Bastos
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal
| | - Fábio Trindade
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal.,Unidade de Investigação Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - João da Costa
- Department of Chemistry, CESAM, University of Aveiro, Aveiro, Portugal
| | - Rita Ferreira
- Department of Chemistry, QOPNA, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
| | - Rui Vitorino
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal.,Unidade de Investigação Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
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Abstract
Adrenomedullin (ADM), the product of the vascular endothelial and smooth muscle cells, and cardiomyocytes, is considered to be a local factor controlling vascular tone, cardiac contractility and renal sodium excretion. The aim of this article was to review the existing data on the effect of different types of exercise on plasma ADM concentration in healthy men. The results of studies on the effect of dynamic exercise on the plasma ADM are contradictory. Some authors reported an increase in plasma ADM, while others showed a slight decrease or did not observe any changes. The inverse relationship between plasma ADM and mean blood pressure observed during maximal exercise support the concept that ADM might blunt the exercise-induced systemic blood pressure increase. Positive relationships between increases in plasma ADM and those in noradrenaline, atrial natriuretic peptide (ANP) or interleukin-6 observed during prolonged exercise suggest that the sympathetic nervous system and cytokine induction may be involved in ADM release. Increased secretion of ADM and ANP during this type of exercise may be a compensatory mechanism attenuating elevation of blood pressure and preventing deterioration of cardiac function. Studies performed during static exercise have showed an increase in plasma ADM only in older healthy men. Positive correlations between increases in plasma ADM and those in noradrenaline and endothelin-1 may indicate the interaction of these hormones in shaping the cardiovascular response to static exercise. Inverse relationships between exercise-induced changes in plasma ADM and those in cardiovascular indices may be at least partly associated with inotropic action of ADM on the heart. Interactions of ADM with vasoactive peptides, catecholamines and hemodynamic factors demonstrate the potential involvement of this peptide in the regulation of blood pressure and myocardial contractility during exercise.
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Affiliation(s)
- Krzysztof Krzeminski
- Department of Applied Physiology, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland
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32
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Supeł K, Kacprzak M, Zielińska M. The prognostic value of MR-proadrenomedullin in patients with acute coronary syndrome complicated by cardiogenic shock. Biomarkers 2016; 22:296-303. [DOI: 10.1080/1354750x.2016.1252962] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Karolina Supeł
- Department of Interventional Cardiology and Electrocardiology, Intensive Cardiac Therapy Clinic, Medical University of Lodz, Poland
| | - Michał Kacprzak
- Department of Interventional Cardiology and Electrocardiology, Intensive Cardiac Therapy Clinic, Medical University of Lodz, Poland
| | - Marzenna Zielińska
- Department of Interventional Cardiology and Electrocardiology, Intensive Cardiac Therapy Clinic, Medical University of Lodz, Poland
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Ochoa-Callejero L, Pozo-Rodrigálvarez A, Martínez-Murillo R, Martínez A. Lack of adrenomedullin in mouse endothelial cells results in defective angiogenesis, enhanced vascular permeability, less metastasis, and more brain damage. Sci Rep 2016; 6:33495. [PMID: 27640364 PMCID: PMC5027589 DOI: 10.1038/srep33495] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/26/2016] [Indexed: 12/28/2022] Open
Abstract
Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine/paracrine function of AM in endothelial cells (EC) in vivo, a conditional knockout of AM in EC (AM(EC-KO)) was used. The amount of vascularization of the matrigel implants was lower in AM(EC-KO) mice indicating a defective angiogenesis. Moreover, ablation of AM in EC revealed increased vascular permeability in comparison with wild type (WT) littermates. In addition, AM(EC-KO) lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their WT counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis, and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases.
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Affiliation(s)
- Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), C/Piqueras 98, 26006-Logroño. Spain
| | - Andrea Pozo-Rodrigálvarez
- Neurovascular Research Group, Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Av. Doctor Arce 37, 28002-Madrid. Spain
| | - Ricardo Martínez-Murillo
- Neurovascular Research Group, Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Av. Doctor Arce 37, 28002-Madrid. Spain
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), C/Piqueras 98, 26006-Logroño. Spain
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Lauria MR, Standley CA, Sorokin Y, Yelian FD, Cotton DB. Adrenomedullin Levels in Normal and Preeclamptic Pregnancy at Term. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155769900600607] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Michele R. Lauria
- Department of Obstetrics and Gynecology, Division and Maternal-Fetal Medicine, Wayne State University, Detroit, Michigan; Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756
| | | | | | | | - David B. Cotton
- Department of Obstetrics and Gynecology, Division and Maternal-Fetal Medicine, Wayne State University, Detroit, Michigan
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35
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Neumann JT, Schwerg M, Dörr O, Mortensen K, Franzen K, Zeller T, Ojeda F, Blankenberg S, Hamm C, Nef H, Stangl V, Möckel M, Sydow K. Biomarker response and therapy prediction in renal denervation therapy - the role of MR-proadrenomedullin in a multicenter approach. Biomarkers 2016; 22:225-231. [PMID: 27153479 DOI: 10.3109/1354750x.2016.1172112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Renal denervation has been proposed as a therapeutic option in patients with resistant hypertension. Circulating blood borne biomarkers might be helpful to identify individuals responding to RDN therapy. MR-proADM is a strong prognostic marker in patients with cardiovascular disease. The aim of this multicenter study was to evaluate the effect of RDN on MR-proADM concentrations. METHODS AND RESULTS We measured MR-proADM, BNP, and MR-proANP in 110 patients before and after RDN in a multicenter setting. All patients were followed up after 1 and 6 months by office and ambulatory blood pressure (BP) measurements. The mean office BP decreased from 165/89 to 152/87 mmHg 6 months after RDN (systolic: p < 0.001; diastolic: ns), the responder-rate was 74%. Intriguingly MR-proADM concentrations increased from 0.66 to 0.69 nmol/L (p < 0.001) and were significantly associated with reduction of systolic office BP after 6 months in multivariate analyses (coefficient -0.0018, p < 0.001). In therapy-responders MR-proADM concentrations showed a significantly higher increase over time (coefficient 0.0105, p < 0.05), as compared to non-responders. There were no significant differences in BP change for individuals with low and high baseline MR-proADM (BP-Delta low MR-proADM -23/-4 mmHg vs. high MR-proADM -24/-5 mmHg). The natriuretic biomarkers BNP and MR-proANP did not change significantly after 6 months. Biomarkers at baseline were not able to predict for therapy-responder. CONCLUSION In patients undergoing RDN, baseline measurements of various biomarkers had no prognostic use for therapy success in this short time follow-up period in a multicenter approach. Intriguingly, MR-proADM showed a significant association with BP reduction after 6 months.
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Affiliation(s)
- Johannes Tobias Neumann
- a Department of General and Interventional Cardiology , Hamburg University Heart Center , Hamburg , Germany
| | - Marius Schwerg
- b Department of Cardiology and Division of Emergency Medicine, Campus Virchow Klinikum and Campus Charité Mitte , Charité Universitätsmedizin Berlin , Germany
| | - Oliver Dörr
- c Department of Internal Medicine I, Cardiology/Angiology , Giessen University , Giessen , Germany
| | - Kai Mortensen
- d Department of Medical Clinic II, Cardiology , University of Lübeck , Lübeck , Germany
| | - Klaas Franzen
- d Department of Medical Clinic II, Cardiology , University of Lübeck , Lübeck , Germany
| | - Tanja Zeller
- a Department of General and Interventional Cardiology , Hamburg University Heart Center , Hamburg , Germany
| | - Francisco Ojeda
- a Department of General and Interventional Cardiology , Hamburg University Heart Center , Hamburg , Germany
| | - Stefan Blankenberg
- a Department of General and Interventional Cardiology , Hamburg University Heart Center , Hamburg , Germany
| | - Christian Hamm
- c Department of Internal Medicine I, Cardiology/Angiology , Giessen University , Giessen , Germany
| | - Holger Nef
- c Department of Internal Medicine I, Cardiology/Angiology , Giessen University , Giessen , Germany
| | - Verena Stangl
- b Department of Cardiology and Division of Emergency Medicine, Campus Virchow Klinikum and Campus Charité Mitte , Charité Universitätsmedizin Berlin , Germany
| | - Martin Möckel
- b Department of Cardiology and Division of Emergency Medicine, Campus Virchow Klinikum and Campus Charité Mitte , Charité Universitätsmedizin Berlin , Germany
| | - Karsten Sydow
- a Department of General and Interventional Cardiology , Hamburg University Heart Center , Hamburg , Germany
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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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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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38
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The Renal Protective Effect of Jiangya Tongluo Formula, through Regulation of Adrenomedullin and Angiotensin II, in Rats with Hypertensive Nephrosclerosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:428106. [PMID: 26557147 PMCID: PMC4628676 DOI: 10.1155/2015/428106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 02/23/2015] [Accepted: 03/12/2015] [Indexed: 01/13/2023]
Abstract
We investigated the effect of Jiangya Tongluo (JYTL) formula on renal function in rats with hypertensive nephrosclerosis. A total of 21 spontaneously hypertensive rats (SHRs) were randomized into 3 groups: valsartan (10 mg/kg/d valsartan), JYTL (14.2 g/kg/d JYTL), and a model group (5 mL/kg/d distilled water); Wistar Kyoto rats comprised the control group (n = 7, 5 mL/kg/d distilled water). Treatments were administered by gavage every day for 8 weeks. Blood pressure, 24-h urine protein, pathological changes in the kidney, serum creatinine, and blood urea nitrogen (BUN) levels were estimated. The contents of adrenomedullin (ADM) and angiotensin II (Ang II) in both the kidney and plasma were evaluated. JYTL lowered BP, 24-h urine protein, serum creatinine, and BUN. ADM content in kidneys increased and negatively correlated with BP, while Ang II decreased and negatively correlated with ADM, but there was no statistically significant difference of plasma ADM between the model and the treatment groups. Possibly, activated intrarenal renin-angiotensin system (RAS) plays an important role in hypertensive nephrosclerosis and the protective function of ADM via local paracrine. JYTL may upregulate endogenous ADM level in the kidneys and antagonize Ang II during vascular injury by dilating renal blood vessels.
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39
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Mid-regional-pro-adrenomedullin plasma levels are increased in obese adolescents. Eur J Nutr 2015; 55:1255-60. [PMID: 26018656 DOI: 10.1007/s00394-015-0938-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 05/20/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE Recently, adrenomedullin (ADM) was defined as a new member of the adipokine family. ADM secreted by adipocytes, through its vasodilator and antioxidant actions, might be protective against metabolic syndrome-associated cardiovascular complications. The aim of the study was to assess plasma mid-regional (MR)-proADM levels in obese adolescents compared to normal-weight subjects and its relation with BMI, body composition and metabolic indices. METHODS Plasma MR-proADM was measured in 32 healthy adolescents [BMI z-score (mean ± SEM) = 0.6 ± 0.09 and 0.8 ± 0.07 in females and males, respectively] and in 51 age-matched obese adolescents [BMI z-score (mean ± SEM) = 2.8 ± 0.12 and 2.9 ± 0.08 in female and males, respectively] by a time-resolved amplified cryptate emission technology assay. RESULTS Plasma MR-proADM levels resulted significantly higher in obese than in normal-weight adolescents (MR-proADM: 0.33 ± 0.1 vs 0.40 ± 0.1 nmol/L, p < 0.0001). Using univariate analysis, we observed that MR-proADM correlated significantly with BMI z-score (p < 0.0001), fat mass (p < 0.0001), circulating insulin (p < 0.004), HOMA-IR (p < 0.005), total cholesterol (p < 0.03) and LDL-cholesterol (p < 0.05). Including MR-proADM as response variable and its significant correlates into a multiple regression analysis, we observed that fat mass (p = 0.014) and BMI z-score (p = 0.036) were independent determinants of circulating MR-proADM. CONCLUSIONS Our study shows for the first time that obese adolescents have higher circulating levels of MR-proADM compared with normal-weight, appropriate controls suggesting its important involvement in obese patients.
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40
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Hussain QA, McKay IJ, Gonzales-Marin C, Allaker RP. Detection of adrenomedullin and nitric oxide in different forms of periodontal disease. J Periodontal Res 2015; 51:16-25. [DOI: 10.1111/jre.12273] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2015] [Indexed: 11/29/2022]
Affiliation(s)
- Q. A. Hussain
- Institute of Dentistry; Barts and The London School of Medicine & Dentistry; Queen Mary University of London; London UK
| | - I. J. McKay
- Institute of Dentistry; Barts and The London School of Medicine & Dentistry; Queen Mary University of London; London UK
| | - C. Gonzales-Marin
- Institute of Dentistry; Barts and The London School of Medicine & Dentistry; Queen Mary University of London; London UK
| | - R. P. Allaker
- Institute of Dentistry; Barts and The London School of Medicine & Dentistry; Queen Mary University of London; London UK
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Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, Truty M, Petersen GM, Kaufman RJ, Chari ST, Mukhopadhyay D. Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction. Clin Cancer Res 2015; 21:1722-33. [PMID: 25355928 PMCID: PMC4383684 DOI: 10.1158/1078-0432.ccr-14-2022] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 10/11/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. EXPERIMENTAL METHODS We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. RESULTS Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. CONCLUSIONS Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.
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Affiliation(s)
- Naureen Javeed
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Gunisha Sagar
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Shamit K Dutta
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Julie S Lau
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Santanu Bhattacharya
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Mark Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Randal J Kaufman
- Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, California
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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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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Korc M. Pancreatic cancer-associated diabetes is an "exosomopathy". Clin Cancer Res 2015; 21:1508-10. [PMID: 25645860 DOI: 10.1158/1078-0432.ccr-14-2990] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 01/29/2015] [Indexed: 01/22/2023]
Abstract
Diabetes may be a consequence of pancreatic cancer, preceding cancer diagnosis. The underlying mechanism is the release of exosomes delivering adrenomedullin to β cells, inducing endoplasmic reticulum stress and perturbations in the unfolded protein response, leading to β-cell dysfunction and death. This knowledge could lead to improved diagnostic strategies for pancreatic cancer.
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Affiliation(s)
- Murray Korc
- Department of Medicine, and Biochemistry and Molecular Biology, The Melvin and Bren Simon Cancer Center, and the Center for Pancreatic Cancer Research, Indiana University School of Medicine, Indianapolis, Indiana.
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Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Shindo T. Adrenomedullin-RAMP2 System in Vascular Endothelial Cells. J Atheroscler Thromb 2015; 22:647-53. [DOI: 10.5551/jat.29967] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine
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Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, Truty M, Petersen GM, Kaufman RJ, Chari ST, Mukhopadhyay D. Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction. Clin Cancer Res 2014. [PMID: 25355928 DOI: 10.1158/1078-0432.ccr-14-2022.pancreatic] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. EXPERIMENTAL METHODS We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. RESULTS Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. CONCLUSIONS Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.
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Affiliation(s)
- Naureen Javeed
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Gunisha Sagar
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Shamit K Dutta
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Julie S Lau
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Santanu Bhattacharya
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Mark Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Randal J Kaufman
- Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, California
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Xue Y, Iqbal N, Chan J, Maisel A. Biomarkers in Hypertension and Their Relationship with Myocardial Target-Organ Damage. Curr Hypertens Rep 2014; 16:502. [DOI: 10.1007/s11906-014-0502-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Passaglia P, Gonzaga NA, Tirapelli DPC, Tirapelli LF, Tirapelli CR. Pharmacological characterisation of the mechanisms underlying the relaxant effect of adrenomedullin in the rat carotid artery. ACTA ACUST UNITED AC 2014; 66:1734-46. [PMID: 25117796 DOI: 10.1111/jphp.12299] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 07/04/2014] [Indexed: 12/28/2022]
Abstract
OBJECTIVES We investigated the mechanisms underlying the relaxant effect of adrenomedullin (AM) in the rat carotid artery and verified the expression of AM system components in this tissue. METHODS The carotid artery was isolated from male Wistar rats and immunohistochemical, Western immunoblotting, real-time polymerase chain reaction and functional assays were conducted. KEY FINDINGS Protein and mRNA expression of AM, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP)1, 2, 3 were detected in carotid segments from male Wistar rats. Immunohistochemical assays showed that AM and CRLR receptors are expressed in the endothelium and smooth muscle cells. Functional assays showed that AM concentration dependently relaxed carotid rings with intact endothelium. Endothelial removal reduced, but not abolished, the relaxation induced by AM. AM22-52 (selective antagonist for AM receptors) and calcitonin gene-related peptide (CGRP)8-37 (selective CGRP receptor antagonist) reduced AM-induced relaxation in endothelium-intact rings. Pre-incubation of endothelium-intact rings with N-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or Rp-8-Bromo-?-phenyl-1,N2-ethenoguanosine 3',5'cyclic monophosphorothioate reduced AM-induced relaxation. Inhibition of cyclooxygenase-1 and protein kinase A (PKA) reduced AM-induced relaxation. The relaxation induced by AM was attenuated by the K(+) channel blockers apamin and glibenclamide. AM increased nitrate levels and 6-keto-prostaglandin F1α (stable product of prostacyclin) in the rat carotid. In endothelium-denuded rings, AM22-52 , glibenclamide and PKA inhibition by H89 reduced AM-induced relaxation. CONCLUSIONS The novelty of this work is that it first demonstrated functionally that AM-induced relaxation is mediated by AM and CGRP receptors located on the endothelium and AM receptors located on smooth muscle of rat carotid arteries. AM-induced relaxation involves the nitric oxide-cGMP pathway, a vasodilator prostanoid, the opening of K(+) channels and the activation of PKA.
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Affiliation(s)
- Patrícia Passaglia
- Programa de pós-graduação em Toxicologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil
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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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Wang CL, Lin HY, Xu JW, Jiang FF, Yang M, Wang JH, Huang XQ. Blood levels of adrenomedullin on admission predict outcomes after acute intracerebral hemorrhage. Peptides 2014; 54:27-32. [PMID: 24457114 DOI: 10.1016/j.peptides.2014.01.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 01/12/2014] [Accepted: 01/13/2014] [Indexed: 11/29/2022]
Abstract
Increased plasma adrenomedullin level has been associated with critical illness. This study aimed to investigate the correlations of plasma adrenomedullin concentration with 3-month clinical outcomes and early neurological deterioration of patients with acute intracerebral hemorrhage. One hundred fourteen patients and 112 healthy controls were recruited. Relationships of plasma adrenomedullin concentrations with early neurological deterioration, 3-month mortality and unfavorable outcome (modified Rankin Scale score >2) were evaluated. Plasma adrenomedullin concentrations were increased in patients than in healthy individuals and were highly associated with National Institutes of Health Stroke Scale scores. A multivariate analysis selected plasma adrenomedullin concentration as an independent predictor for 3-month clinical outcomes and early neurological deterioration. A receiver operating characteristic curve analysis showed plasma adrenomedullin concentration predicted 3-month clinical outcomes and early neurological deterioration with high area under curves. The predictive value of adrenomedullin was similar to that of National Institutes of Health Stroke Scale score. In a combined logistic-regression model, adrenomedullin did not improve the predictive value of National Institutes of Health Stroke Scale score. Thus, elevated plasma adrenomedullin concentration is highly associated with 3-month clinical outcomes and early neurological deterioration of patients with acute intracerebral hemorrhage.
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Affiliation(s)
- Chuan-Liu Wang
- Department of Neurology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
| | - Hai-Yan Lin
- Department of Neurology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China.
| | - Jian-Wei Xu
- Department of Urology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
| | - Fei-Fei Jiang
- Department of Neurology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
| | - Ming Yang
- Department of Neurology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
| | - Jin-Hua Wang
- Department of Neurology, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
| | - Xiu-Qing Huang
- Department of Rehabilitation, Quzhou People's Hospital, 2 Zhongloudi Road, Kecheng District, Quzhou 324000, China
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Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PLoS One 2014; 9:e87667. [PMID: 24505304 PMCID: PMC3914859 DOI: 10.1371/journal.pone.0087667] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Accepted: 12/29/2013] [Indexed: 11/19/2022] Open
Abstract
Various bioactive peptides have been implicated in the homeostasis of organs and tissues. Adrenomedullin (AM) is a peptide with various bioactivities. AM-receptor, calcitonin-receptor-like receptor (CLR) associates with one of the subtypes of the accessory proteins, RAMPs. Among the RAMP subisoforms, only RAMP2 knockout mice (−/−) reproduce the phenotype of embryonic lethality of AM−/−, illustrating the importance of the AM-RAMP2-signaling system. Although AM and RAMP2 are abundantly expressed in kidney, their function there remains largely unknown. We used genetically modified mice to assess the pathophysiological functions of the AM-RAMP2 system. RAMP2+/− mice and their wild-type littermates were used in a streptozotocin (STZ)-induced renal injury model. The effect of STZ on glomeruli did not differ between the 2 types of mice. On the other hand, damage to the proximal urinary tubules was greater in RAMP2+/−. Tubular injury in RAMP2+/− was resistant to correction of blood glucose by insulin administration. We examined the effect of STZ on human renal proximal tubule epithelial cells (RPTECs), which express glucose transporter 2 (GLUT2), the glucose transporter that specifically takes up STZ. STZ activated the endoplasmic reticulum (ER) stress sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK). AM suppressed PERK activation, its downstream signaling, and CCAAT/enhancer-binding homologous protein (CHOP)-induced cell death. We confirmed that the tubular damage was caused by ER stress-induced cell death using tunicamycin (TUN), which directly evokes ER stress. In RAMP2+/− kidneys, TUN caused severe injury with enhanced ER stress. In wild-type mice, TUN-induced tubular damage was reversed by AM administration. On the other hand, in RAMP2+/−, the rescue effect of exogenous AM was lost. These results indicate that the AM-RAMP2 system suppresses ER stress-induced tubule cell death, thereby exerting a protective effect on kidney. The AM-RAMP2 system thus has the potential to serve as a therapeutic target in kidney disease.
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