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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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Nakhaie S, Yazdani R, Shakibi M, Torabian S, Pezeshki S, Bazrafshani MS, Azimi M, Salajegheh F. The effects of antihypertensive medications on severity and outcomes of hypertensive patients with COVID-19. J Hum Hypertens 2023; 37:511-518. [PMID: 35790875 PMCID: PMC9255835 DOI: 10.1038/s41371-022-00716-7] [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: 06/30/2021] [Revised: 02/19/2022] [Accepted: 06/14/2022] [Indexed: 02/03/2023]
Abstract
In Covid-19 pandemic, specific comorbidities are associated with the increased risk of worse outcomes and increased severity of lung injury and mortality. the aim of this study was to investigate the effects of antihypertensive medications on the severity and outcomes of hypertensive patients with COVID-19. This retrospective observational study conducted on patients with COVID-19 who referred to Afzalipour Hospital, Kerman, Iran during the six months from 19 February 2020 to 20 July 2020. The data were collected through medical chart reviews. We assessed 265 patients with Covid-19 and they stratified based on hypertension and type of antihypertension medications. The data were described and Student's t-test, Mann-Whitney U and Fisher exact test were run to compare the patients 'demographical and clinical information. The qualitative variables were compared using the by SPSS software version 23. The results of the present study showed that hypertension was a prevalent comorbidity among patients with COVID-19 and hypertensive patients compared to other patients without any comorbidity who were older (P-value: 0.03). The oxygen saturation was higher for the patients in the control group than hypertensive patients (P-value: 0.01). The severity of COVID-19 and its outcome were not different between the patients who took or did not take antihypertensive medications and also the type of antihypertensive medications. Hypertensive patients did not show any significant difference in survival, hospital stay, ICU admission, disease severity, and invasive medical ventilation in other normotensive patients with COVID-19.
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Affiliation(s)
- Samira Nakhaie
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Rostam Yazdani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammadreza Shakibi
- HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Soheila Torabian
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Pezeshki
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Maliheh Sadat Bazrafshani
- HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Azimi
- Department of Traditional Medicine, School of Traditional Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Faranak Salajegheh
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
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3
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Iwao M, Tanaka R, Suzuki Y, Nakata T, Aoki K, Fukuda A, Fukunaga N, Tatsuta R, Ohno K, Shibata H, Itoh H. Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control. Sci Rep 2021; 11:21931. [PMID: 34754024 PMCID: PMC8578546 DOI: 10.1038/s41598-021-01403-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 10/07/2021] [Indexed: 11/09/2022] Open
Abstract
Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r = - 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.
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Affiliation(s)
- Motoshi Iwao
- Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan
| | - Ryota Tanaka
- Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan.
| | - Yosuke Suzuki
- Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Noshio, Tokyo, Japan
| | - Takeshi Nakata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Kohei Aoki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Akihiro Fukuda
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Naoya Fukunaga
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Ryosuke Tatsuta
- Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan
| | - Keiko Ohno
- Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Noshio, Tokyo, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Hiroki Itoh
- Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan
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Kato J, Kawagoe Y, Jiang D, Ida T, Shimamoto S, Igarashi K, Kitamura K. Plasma adrenomedullin level and year-by-year variability of body mass index in the general population. Peptides 2021; 142:170567. [PMID: 33964322 DOI: 10.1016/j.peptides.2021.170567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/26/2022]
Abstract
Plasma levels of the hypotensive peptides of adrenomedullin and atrial and B-type natriuretic peptides (AM, ANP, BNP) are possible biomarkers for cardiovascular diseases. Increased variability of body mass index (BMI) over a certain period of time has been reported to be associated with cardiovascular morbidity or mortality. The aim of this study is to examine clinical significance of those hypotensive peptides as biomarkers by analyzing the relationship between plasma levels of the peptides and year-by-year variability of BMI in the general population without overt cardiovascular diseases. The subjects were 427 local residents (141 males and 286 females) attending their annual health check-up, who had been examined at least 5 times over the preceding period of 10 years. They were divided into two groups of low or high variability by the median of coefficient of variation (CV) of BMI values for each gender. Plasma AM levels of those with high year-by-year variability of BMI were significantly increased, as compared to the group with low variability, in both genders; meanwhile, such a difference was not noted in plasma levels of the natriuretic peptides. No significant differences were found in the basal parameters, which could affect plasma AM level, such as age, BMI, blood pressure or serum creatinine, between two groups. In conclusion, increase in plasma AM was associated with high year-by-year variability of BMI in the general population without overt heart disease. This relationship between the two suggests that increased plasma AM level is a cardiovascular risk marker.
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Affiliation(s)
- Johji Kato
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan; Cardiovascular Medicine, University of Miyazaki Hospital, Kiyotake, Miyazaki, 889-1692, Japan.
| | - Yukiko Kawagoe
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan
| | - Danfeng Jiang
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan
| | - Takanori Ida
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan
| | - Satoshi Shimamoto
- Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Kanagawa, 252-1123, Japan
| | - Koji Igarashi
- Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Kanagawa, 252-1123, Japan
| | - Kazuo Kitamura
- Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan
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Accelerated DNA methylation age and medication use among African Americans. Aging (Albany NY) 2021; 13:14604-14629. [PMID: 34083497 PMCID: PMC8221348 DOI: 10.18632/aging.203115] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 05/14/2021] [Indexed: 12/16/2022]
Abstract
DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.
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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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7
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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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Zhou PH, Shi L, Hu W, Zhang XB, Wang W, Zhang LJ. Changes of adrenomedullin and natriuretic peptides in patients with adrenal medullary hyperplasia prior to and following pharmacological therapy and adrenalectomy. Exp Ther Med 2016; 12:864-872. [PMID: 27446289 PMCID: PMC4950839 DOI: 10.3892/etm.2016.3418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 05/16/2016] [Indexed: 12/17/2022] Open
Abstract
The aim of the present study was to investigate the pathophysiological functions of adrenomedullin (ADM), atrial and brain natriuretic peptides (ANP and BNP) in patients with adrenal medullary hyperplasia (AMH). Plasma ADM, ANP and BNP concentrations were measured in 20 patients with AMH, 35 patients with essential hypertension (EH), and 40 healthy control subjects. Following effective antihypertensive therapy, the values in AMH and EH patients were measured again and laparoscopic adrenalectomy was performed for AMH patients. At 2 weeks after surgery, the three peptides were measured again. The AMH patients had higher plasma concentrations of ADM, ANP and BNP compared with the EH and control subjects. There were significant differences in the values of ADM, ANP and BNP between adrenal vein and inferior vena cava and between AMH and contralateral adrenal vein. Plasma ADM concentration was correlated with serum epinephrine and norepinephrine and urine vanillylmandelic acid, in addition to systolic and diastolic blood pressure, left ventricular ejection fraction, left ventricular mass index and ANP and BNP values in the AMH group. Following antihypertensive treatment, ADM, ANP and BNP were significantly decreased in EH patients, but remained unchanged in AMH subjects. However, these concentrations significantly decreased following surgery. Therefore, the present results suggest that ADM, ANP and BNP may be involved in regulating adrenal medulla functions.
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Affiliation(s)
- Pang-Hu Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lei Shi
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Hu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao-Bin Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Li-Jun Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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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: 127] [Impact Index Per Article: 12.7] [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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Hu W, Shi L, Zhou PH, Zhang XB. Plasma concentrations of adrenomedullin and atrial and brain natriuretic peptides in patients with adrenal pheochromocytoma. Oncol Lett 2015; 10:3163-3170. [PMID: 26722306 DOI: 10.3892/ol.2015.3660] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 08/05/2015] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to evaluate any changes in the plasma concentrations of adrenomedullin (ADM), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with adrenal pheochromocytoma (PC). The plasma concentrations of the three peptides were measured in 45 healthy control individuals and 90 untreated patients with PC, who consisted of 20 normotensive patients, 30 borderline hypertensive patients and 40 hypertensive patients. After 4 weeks of effective antihypertensive therapy for hypertensive PC patients, the concentrations of ADM, ANP and BNP were measured again, and laparoscopic adrenalectomy was then performed for all PC patients with values that were measured 2 weeks later. The plasma concentrations of the three peptides were significantly increased in the borderline hypertensive and hypertensive patients compared with the concentrations in control individuals and normotensive patients. In addition, there were significant differences between the levels of ADM, ANP and BNP in the borderline and hypertensive groups. The plasma ADM concentration was not associated with the blood urea nitrogen levels, serum creatinine levels or glomerular filtration rate, but was correlated with the serum epinephrine, serum norepinephrine and urine vanillylmandelic acid levels. In addition, the ADM concentration was associated with the systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular mass index and plasma concentrations of ANP and BNP in the hypertensive patients with PC. After 4 weeks of antihypertensive treatment, the values of the three peptides in the hypertensive patients with PC were not significantly changed. As expected, the values in borderline and hypertensive groups were significantly decreased 2 weeks subsequent to surgery, whereas there were no significant changes in the normotensive group. ADM may participate, along with ANP and BNP, in the mechanisms that counteract further elevation of blood pressure in patients with PC, and there may be an ADM/catecholamine local regulatory mechanism that is important for the control of adrenal medulla functions.
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Affiliation(s)
- Wei Hu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lei Shi
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Pang-Hu Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao-Bin Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Hu W, Zhou PH, Zhang XB, Xu CG, Wang W. Plasma concentrations of adrenomedullin and natriuretic peptides in patients with essential hypertension. Exp Ther Med 2015; 9:1901-1908. [PMID: 26136912 DOI: 10.3892/etm.2015.2345] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 02/16/2015] [Indexed: 11/05/2022] Open
Abstract
This study was designed to assess any changes in the plasma concentrations of adrenomedullin (ADM) and atrial and brain natriuretic peptide (ANP and BNP, respectively), and to investigate their pathophysiological roles in patients with essential hypertension (EH). The plasma ADM, ANP and BNP concentrations were measured in 64 patients with untreated EH and 35 normotensive control subjects. After 4 weeks of effective antihypertensive therapy with oral drugs for the hypertensive patients, the plasma concentrations of ADM, ANP and BNP in the hypertensive patients were measured again. The plasma concentrations of ADM, ANP and BNP were significantly higher in the hypertensive patients than those in the control subjects, and the concentrations increased with the clinical stage. Furthermore, the hypertensive patients exhibited increased mean arterial pressure (MAP), blood urea nitrogen (BUN), serum creatinine (Scr) and decreased glomerular filtration rates (GFRs) compared with the control subjects. The plasma ADM concentration was not only correlated with BUN, Scr and the GFR, but was also associated with the MAP and the plasma levels of ANP and BNP. Following effective antihypertensive therapy with oral medication for 4 weeks, the plasma concentrations of ADM, ANP and BNP were significantly, but not sharply, decreased. In conclusion, ADM, along with ANP and BNP, may be involved in the mechanisms acting against a further increase in blood pressure and may be useful biomarkers for the diagnosis and treatment of hypertensive patients.
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Affiliation(s)
- Wei Hu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Pang-Hu Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao-Bin Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Chang-Geng Xu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Hu W, Zhou PH, Zhang XB, Xu CG, Wang W. Pathophysiological functions of adrenomedullin and natriuretic peptides in patients with primary aldosteronism. Endocrine 2015; 48:661-8. [PMID: 25027294 DOI: 10.1007/s12020-014-0316-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 05/21/2014] [Indexed: 11/25/2022]
Abstract
To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow-release nifedipine, the three peptides were measured again in the PA and low-renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low-renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions.
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Affiliation(s)
- Wei Hu
- Department of Urology, Renmin Hospital of Wuhan University, 238# Liberation Road, Wuhan, 430060, Hubei Province, China
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Suzuki Y, Itoh H, Katagiri F, Sato F, Kawasaki K, Sato Y, Sato Y, Mimata H, Takeyama M. Relationship between plasma mid-regional pro-adrenomedullin level and resistance to antihypertensive therapy in stable kidney transplant recipients. Peptides 2013; 48:45-8. [PMID: 23954711 DOI: 10.1016/j.peptides.2013.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 08/02/2013] [Accepted: 08/02/2013] [Indexed: 11/20/2022]
Abstract
We investigated the relationship between plasma mid-regional pro-adrenomedullin (MR-proADM)-like immunoreactive substance (IS) level and clinical characteristics associated with renal failure or resistance to antihypertensive therapy in stable kidney transplant recipients. Forty-six Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. To evaluate resistance to antihypertensive therapy, we calculated the treatment intensity score of the antihypertensive drugs in each recipient. Morning blood samples were collected and plasma MR-proADM-IS levels were measured using an enzyme immunoassay. A significant correlation was observed between plasma MR-proADM-IS level with creatinine clearance or treatment intensity score. Multiple regression analysis identified plasma MR-proADM level and body mass index as significant independent factors associated with treatment intensity score. Plasma MR-proADM level may be a useful biomarker indicating the degree of resistance to antihypertensive therapy.
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Affiliation(s)
- Yosuke Suzuki
- Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita 879-5593, Japan.
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Kong DG, Gao H, Lu YQ, Qi XW, Ma LL, Kong XQ, Yao DK, Wang LX. Anxiety disorders are associated with increased plasma adrenomedullin level and left ventricular hypertrophy in patients with hypertension. Clin Exp Hypertens 2013; 36:27-31. [PMID: 23638647 DOI: 10.3109/10641963.2013.783049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To investigate the association between anxiety disorders and left ventricular hypertrophy in patients with essential hypertension. METHODS Left ventricular structure and function were assessed with echocardiography in 56 patients with essential hypertension and anxiety disorder (study group) and in 56 patients with hypertension only (control group). Serum adrenomedullin levels were also measured in these patients. RESULTS There was no statistically significant difference in the left ventricular ejection fraction between the study and the control group (54.21 ± 88.81% versus 56.01 ± 7.85%, p>0.05). The left ventricular mass index (LVMI) in study group was higher than in control group (137.05 ± 9.42 versus 123.57 ± 7.01 g/m(2), p=0.001). The plasma levels of adrenomedullin in study group was higher than in control group (25.97 ± 5.48 versus 18.32 ± 6.97 ng/L, p=0.001). Levels of plasma adrenomedullin were positively correlated with LVMI in the study (r=0.734, p<0.05) and control group (r=0.592, p<0.05). CONCLUSION Anxiety disorders are associated with elevated plasma adrenomedullin levels and increased left ventricular hypertrophy in patients with essential hypertension. The clinical significance of these changes requires further investigation.
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Affiliation(s)
- De-Gui Kong
- Department of Cardiology, Liaocheng People's Hospital of Taishan Medical University , Shandong Province 252000 , China
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Sahin I, Celik O, Celik N, Keskin L, Dogru A, Dogru I, Yürekli M, Yologlu S. Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome. J Endocrinol Invest 2012; 35:553-6. [PMID: 21791966 DOI: 10.3275/7872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.
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Affiliation(s)
- I Sahin
- Endocrinology and Metabolism, Inönü University, Malatya, Turkey.
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Cheung BMY, Ong KL, Tso AWK, Leung RYH, Cherny SS, Sham PC, Lam TH, Lam KSL. Plasma adrenomedullin level is related to a single nucleotide polymorphism in the adrenomedullin gene. Eur J Endocrinol 2011; 165:571-7. [PMID: 21798961 DOI: 10.1530/eje-11-0513] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Adrenomedullin (ADM) plays an important role in inflammation and is a marker of future cardiovascular events. We studied common single nucleotide polymorphisms (SNPs) in the gene encoding ADM and their relationship with the plasma levels of ADM and other inflammatory markers. DESIGN AND METHODS Plasma ADM, interleukin 6 (IL6), fibrinogen, and C-reactive protein (CRP) were measured in 476 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study-2. Four tag SNPs in ADM were genotyped. RESULTS Plasma ADM level increased with decreasing plasma IL6 level (β=-0.116, P=0.014). Plasma ADM level was not related to plasma levels of CRP and fibrinogen, and other clinical characteristics, except age (P=0.049). The four SNPs, rs3814700, rs11042725, rs34354539, and rs4910118, had minor allele frequencies of 31.1, 28.7, 33.8, and 23.4% respectively. Carriers of the minor allele of rs4910118 had a mean plasma ADM level that was 10.5% (95% confidential interval: 2.5-17.8%) lower than the non-carriers (β=-0.115, P=0.011). Haplotype analysis revealed a similar significant association with plasma ADM (P=0.040). In multivariate analysis, the presence of the minor allele of rs4910118, but not plasma IL6, was independently associated with plasma ADM (P=0.010). CONCLUSION Plasma ADM correlates with plasma IL6 level, consistent with its role in inflammation. It is related to an SNP common in Chinese, independent of other covariates. ADM genotype should be included in future studies of cardiovascular risk prediction.
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Affiliation(s)
- Bernard M Y Cheung
- Department of Medicine, Research Centre of Heart, Brain, Hormone and Healthy Aging, School of Public Health, University of Hong Kong, Hong Kong, People's Republic of China.
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Ong KL, Tso AWK, Leung RYH, Cherny SS, Sham PC, Lam TH, Cheung BMY, Lam KSL. A genetic variant in the gene encoding adrenomedullin predicts the development of dysglycemia over 6.4 years in Chinese. Clin Chim Acta 2010; 412:353-7. [PMID: 21075100 DOI: 10.1016/j.cca.2010.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 11/04/2010] [Accepted: 11/04/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND Adrenomedullin, a vasodilatory peptide, facilitates the differentiation of pre-adipocytes, and affects lipolysis and glucose uptake. We investigated the association of common single nucleotide polymorphisms (SNPs) in the gene encoding adrenomedullin (ADM) with dysglycemia in the Hong Kong Chinese population. METHODS Four SNPs were genotyped in 1391 subjects without dysglycemia at baseline from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, which had a median follow-up time of 6.4 years. Dysglycemia included impaired fasting glucose, impaired glucose tolerance, and diabetes according to the WHO 1998 criteria. At follow-up, 382 subjects had developed dysglycemia. RESULTS In stepwise logistic regression, the SNP rs11042725 was a significant independent predictor of the development of dysglycemia (OR=1.31, P=0.012), together with baseline age (P<0.001), plasma triglycerides (P<0.001), body mass index (P=0.004), 2-h glucose after oral glucose tolerance test (P<0.001), homeostasis model assessment of insulin resistance index (P=0.045), and follow-up duration (P=0.009). The association was more significant in women (P=0.002) and in subjects without regular exercise (P=0.001). CONCLUSIONS Our study suggests a potential role of genetic variants in the ADM gene in the development of dysglycemia in our local Chinese population.
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Affiliation(s)
- Kwok Leung Ong
- Department of Medicine, University of Hong Kong, Hong Kong
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Jin D, Otani K, Yamahara K, Ikeda T, Nagaya N, Kangawa K. Adrenomedullin reduces expression of adhesion molecules on lymphatic endothelial cells. ACTA ACUST UNITED AC 2010; 166:21-7. [PMID: 20727374 DOI: 10.1016/j.regpep.2010.08.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 07/26/2010] [Accepted: 08/11/2010] [Indexed: 01/18/2023]
Abstract
Adrenomedullin (AM) is a novel vasoactive peptide which regulates vascular tone and vascular endothelial cell growth. We recently reported that lymphatic endothelial cells (LECs) are also an attractive target of AM and concluded that AM is a potent mediator of lympangiogenesis. In the present study, we conducted a genome-wide analysis of genes that are regulated by AM in LECs. AM profoundly suppressed gene expression of cell adhesion receptors and inflammatory factors in LECs, such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), endothelial adhesion molecule-1 (E-selectin), interleukin-8, and chemokines, QRT-PCR and flow cytometry analysis showed that AM dose-dependently suppressed the TNF-a-induced mRNA and protein expression of ICAM-1 and VCAM-l. Treatment of LECs with a cell permeable cyclic adenosine monophosphate (cAMP) analog, 8-Br-cAMP, mimicked the suppressive effect of AM on the expression of adhesion molecules. Moreover, both AM and 8-Br-cAMP suppressed TNF-α-induced NF-κB activation in LECs, indicating that AM reduces expression of adhesion molecules in LECs via a cAMP/NF-kB dependent pathway. These results suggest that AM may have an important role in the regulation of the expression of adhesion molecules in lymphatic endothelium, which is critical in the control of immune and inflammatory responses.
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Affiliation(s)
- Donghao Jin
- Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan
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Jin D, Harada K, Ohnishi S, Yamahara K, Kangawa K, Nagaya N. Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema. Cardiovasc Res 2008; 80:339-45. [PMID: 18708640 DOI: 10.1093/cvr/cvn228] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
AIMS Adrenomedullin (AM) is a multifunctional peptide hormone that plays a significant role in vasodilation and angiogenesis. Lymphoedema is a common but refractory disorder that is difficult to be treated with conventional therapy. We therefore investigated whether AM promotes lymphangiogenesis and improves lymphoedema. METHODS AND RESULTS The effects of AM on lymphatic endothelial cells (LEC) were investigated. AM promoted proliferation, migration, and network formation of cultured human lymphatic microvascular endothelial cells (HLMVEC). AM increased intracellular cyclic adenosine monophosphate (cAMP) level in HLMVEC. The cell proliferation induced by AM was inhibited by a cAMP antagonist and mitogen-activated protein kinase kinase (MEK) inhibitors. Phosphorylated extracellular signal-regulated kinase (ERK) in HLMVEC was increased by AM. Continuous administration of AM (0.05 microg/kg/min) to BALB/c mice with tail lymphoedema resulted in a decrease in lymphoedema thickness. AM treatment increased the number of lymphatic vessels and blood vessels in the injury site. CONCLUSION AM promoted LEC proliferation at least in part through the cAMP/MEK/ERK pathway, and infusion of AM induced lymphangiogenesis and improved lymphoedema in mice.
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Affiliation(s)
- Donghao Jin
- Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
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Nishikimi T. Do increased plasma adrenomedullin levels in normotensive subjects precede hypertension? J Hum Hypertens 2006; 20:557-9. [PMID: 16855609 DOI: 10.1038/sj.jhh.1002039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- T Nishikimi
- Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
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