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Perez-Ternero C, Li W, Aubdool AA, Goldin RD, Loy J, Devalia K, Alazawi W, Hobbs AJ. Endogenous C-type natriuretic peptide offsets the pathogenesis of steatohepatitis, hepatic fibrosis, and portal hypertension. PNAS NEXUS 2025; 4:pgae579. [PMID: 39816244 PMCID: PMC11734523 DOI: 10.1093/pnasnexus/pgae579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/20/2024] [Indexed: 01/18/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), hepatic fibrosis, and portal hypertension constitute an increasing public health problem due to the growing prevalence of obesity and diabetes. C-type natriuretic peptide (CNP) is an endogenous regulator of cardiovascular homeostasis, immune cell reactivity, and fibrotic disease. Thus, we investigated a role for CNP in the pathogenesis of MASLD. Wild-type (WT), global CNP (gbCNP-/-), and natriuretic peptide receptor-C (NPR-C-/-) knockout mice were fed a choline-deficient defined amino acid diet or administered CCl4. Liver damage was assessed by histological and biochemical analyses, with steatosis and portal vein size determined by ultrasound. Portal vein pressure and reactivity were measured in vivo and ex vivo, respectively. Pharmacological CNP delivery was used to evaluate prospective therapeutic benefit, and plasma CNP concentration was compared in controls and patients with cirrhosis. Circulating CNP concentration was lower in patients with cirrhosis compared with controls. gbCNP-/- mice were more susceptible, versus WT, to advanced steatohepatitis and hepatic fibrosis, characterized by increased immune cell infiltration, fibrosis, ballooning, plasma alanine aminotransferase concentration, and up-regulation of markers driving these processes. gbCNP-/- mice had increased portal vein diameter and pressure, underpinned by CNP insensitivity. NPR-C-/- animals recapitulated, comparatively, the exaggerated pathogenic phenotype in gbCNP-/- mice, whereas CNP reduced hepatic stellate cell proliferation via NPR-B-dependent inhibition of extracellular signal-related kinase 1/2. Administration of CNP reversed many aspects of disease severity. These data define a new intrinsic role for CNP in offsetting the pathogenesis of MASLD, hepatic fibrosis, and portal hypertension and the potential for targeting CNP signaling for treating these disorders.
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Affiliation(s)
- Cristina Perez-Ternero
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Wenhao Li
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom
| | - Aisah A Aubdool
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Robert D Goldin
- Centre for Pathology, St Mary’s Hospital, Imperial College, London W2 1NY, United Kingdom
| | - John Loy
- Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London E9 6SR, United Kingdom
| | - Kalpana Devalia
- Bariatric Surgery Department, Homerton University Hospital, Homerton Row, London E9 6SR, United Kingdom
| | - William Alazawi
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom
| | - Adrian J Hobbs
- Faculty of Medicine and Dentistry, William Harvey Research Institute, Barts and The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
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2
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Mierke CT. Mechanosensory entities and functionality of endothelial cells. Front Cell Dev Biol 2024; 12:1446452. [PMID: 39507419 PMCID: PMC11538060 DOI: 10.3389/fcell.2024.1446452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 10/04/2024] [Indexed: 11/08/2024] Open
Abstract
The endothelial cells of the blood circulation are exposed to hemodynamic forces, such as cyclic strain, hydrostatic forces, and shear stress caused by the blood fluid's frictional force. Endothelial cells perceive mechanical forces via mechanosensors and thus elicit physiological reactions such as alterations in vessel width. The mechanosensors considered comprise ion channels, structures linked to the plasma membrane, cytoskeletal spectrin scaffold, mechanoreceptors, and junctional proteins. This review focuses on endothelial mechanosensors and how they alter the vascular functions of endothelial cells. The current state of knowledge on the dysregulation of endothelial mechanosensitivity in disease is briefly presented. The interplay in mechanical perception between endothelial cells and vascular smooth muscle cells is briefly outlined. Finally, future research avenues are highlighted, which are necessary to overcome existing limitations.
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Dickinson YA, Moyes AJ, Hobbs AJ. C-type natriuretic peptide (CNP): The cardiovascular system and beyond. Pharmacol Ther 2024; 262:108708. [PMID: 39154787 DOI: 10.1016/j.pharmthera.2024.108708] [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: 03/28/2024] [Revised: 07/30/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
C-type natriuretic peptide (CNP) represents the 'local' member of the natriuretic peptide family, functioning in an autocrine or paracrine capacity to modulate a hugely diverse portfolio of physiological processes. Whilst the best-characterised of these regulatory roles are in the cardiovascular system, akin to its predominantly endocrine siblings atrial (ANP) and brain (BNP) natriuretic peptides, CNP governs many additional, unrelated mechanisms including bone growth, gamete maturation, auditory processing, and neuronal integrity. Furthermore, there is currently great interest in mimicking the biological activity of CNP for therapeutic gain in many of these disparate organ systems. Herein, we provide an overview of the physiology, pathophysiology and pharmacology of CNP in both cardiovascular and non-cardiovascular settings.
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Affiliation(s)
- Yasmin A Dickinson
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Amie J Moyes
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Adrian J Hobbs
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
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Katoh K. Effects of Mechanical Stress on Endothelial Cells In Situ and In Vitro. Int J Mol Sci 2023; 24:16518. [PMID: 38003708 PMCID: PMC10671803 DOI: 10.3390/ijms242216518] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Endothelial cells lining blood vessels are essential for maintaining vascular homeostasis and mediate several pathological and physiological processes. Mechanical stresses generated by blood flow and other biomechanical factors significantly affect endothelial cell activity. Here, we review how mechanical stresses, both in situ and in vitro, affect endothelial cells. We review the basic principles underlying the cellular response to mechanical stresses. We also consider the implications of these findings for understanding the mechanisms of mechanotransducer and mechano-signal transduction systems by cytoskeletal components.
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Affiliation(s)
- Kazuo Katoh
- Laboratory of Human Anatomy and Cell Biology, Faculty of Health Sciences, Tsukuba University of Technology, Tsukuba 305-8521, Japan
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Tsitsikov EN, Phan KP, Liu Y, Tsytsykova AV, Kinter M, Selland L, Garman L, Griffin C, Dunn IF. TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. iScience 2023; 26:107474. [PMID: 37583551 PMCID: PMC10424150 DOI: 10.1016/j.isci.2023.107474] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/19/2023] [Accepted: 07/21/2023] [Indexed: 08/17/2023] Open
Abstract
Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similar to Mekk3-, Mek5- or Erk5-deficient mice, Traf7-deficient embryos died in utero around midgestation due to impaired endothelium integrity. They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. In addition, deletion of Traf7 in endothelial cells of postnatal mice was associated with severe cerebral hemorrhage. Here, we show that besides MEKK3 and MEK5, TRAF7 associates with a planar cell polarity protein SCRIB. SCRIB binds with an N-terminal region of TRAF7, while MEKK3 associates with the C-terminal WD40 domain. Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells. These findings suggest that TRAF7 and SCRIB may comprise an upstream part of the MEKK3-MEK5-ERK5 signaling pathway.
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Affiliation(s)
- Erdyni N. Tsitsikov
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Khanh P. Phan
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yufeng Liu
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Alla V. Tsytsykova
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Mike Kinter
- Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Lauren Selland
- Histology, Immunohistochemistry, Microscopy Core-COBRE Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Lori Garman
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Courtney Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Ian F. Dunn
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Karaca C, Bektas M, Dincer MT, Bakkaloglu OK, Cebeci Z, Bakir A, Seyahi N, Trabulus S, Tukek T. NT-proCNP levels predict higher atherosclerotic cardiovascular risk profile in patients with proliferative diabetic retinopathy. Acta Diabetol 2023:10.1007/s00592-023-02095-y. [PMID: 37085633 DOI: 10.1007/s00592-023-02095-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 04/08/2023] [Indexed: 04/23/2023]
Abstract
AIMS In this study, we aimed to demonstrate the effectiveness of serum amino-terminal proCNP (NT-proCNP) levels in predicting coronary heart disease (CHD) and cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. METHODS We recruited 73 patients with T2DM in the study. Additionally, we grouped the patients according to their status of diabetic retinopathy (DR) as no DR, non-proliferative DR, or proliferative DR. Serum NT-proCNP levels of the patients were measured and their atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated. RESULTS There was no significant difference in terms of NT-proCNP levels between the groups (p = 0.3) and in terms of CHD and ASCVD risk scores (p = 0.4 and p = 0.4, respectively). In the correlation analysis, a significant correlation was observed between the NT-proCNP levels and the ASCVD risk score (r = 0.373; p = 0.008 among the entire cohort and r = 0.555; p = 0.01 in the non-proliferative-DR group), smoking status (r = 0.280; p = 0.03 among the entire cohort and r = 0.362; p = 0.035 in the non-proliferative-DR group), sBP (r = 0.278; p = 0.038 among the entire cohort), and dBP (r = 0.284; p = 0.034 among the entire cohort and r = 0.482; p = 0.004 in the proliferative-DR group). In the ROC analysis, we found that the NT-proCNP level predicted a high ASCVD risk score with 83.3% sensitivity and 70.8% specificity and a very high ASCVD risk score with 100% sensitivity and 69.2% specificity among the proliferative-DR patients. No cut-off value was calculated for the prediction of high and very-high ASCVD risk scores in patients with non-proliferative DR. Similarly, no cut-off value was revealed for the prediction of established coronary artery disease in all groups. CONCLUSIONS Our study revealed a significant association between NT-proCNP levels and high ASCVD risk scores in patients with proliferative DR.
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Affiliation(s)
- Cebrail Karaca
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Fatih, 34360, Istanbul, Turkey
| | - Murat Bektas
- Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mevlut T Dincer
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Fatih, 34360, Istanbul, Turkey
| | - Oguz K Bakkaloglu
- Division of Gastroenterohepatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Zafer Cebeci
- Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Alev Bakir
- Department of Social Pediatrics, Institute of Child Health, Istanbul University, Istanbul, Turkey
| | - Nurhan Seyahi
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Fatih, 34360, Istanbul, Turkey
| | - Sinan Trabulus
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Fatih, 34360, Istanbul, Turkey.
| | - Tufan Tukek
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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7
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Mavragani A, Pearson JF, Troughton RW, Kennedy MA, Espiner EA. The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study. JMIR Res Protoc 2023; 12:e37011. [PMID: 36630163 PMCID: PMC9878369 DOI: 10.2196/37011] [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: 02/02/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations-higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. OBJECTIVE The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. METHODS All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Māori or Pacifica ethnicity) participating in the original CHALICE study-free of history of heart or renal disease at age 50 years and who consented to further study-will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. RESULTS The study will commence in 2022 and be completed in 2024. CONCLUSIONS Proving our hypothesis-that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively-opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/37011.
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Affiliation(s)
| | - John F Pearson
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.,Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
| | - Richard W Troughton
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christcurch, New Zealand
| | - Martin A Kennedy
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Eric A Espiner
- Christchurch Heart Institute, Department of Medicine, University of Otago, Christcurch, New Zealand
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Physiological and Pathophysiological Effects of C-Type Natriuretic Peptide on the Heart. BIOLOGY 2022; 11:biology11060911. [PMID: 35741432 PMCID: PMC9219612 DOI: 10.3390/biology11060911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/30/2022] [Accepted: 06/08/2022] [Indexed: 01/06/2023]
Abstract
Simple Summary C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), CNP was not previously regarded as an important cardiac modulator. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with its cognate natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. In this review, I introduce the history of research on CNP in the cardiac field. Abstract C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike other members, i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are cardiac hormones secreted from the atrium and ventricle of the heart, respectively, CNP is regarded as an autocrine/paracrine regulator with broad expression in the body. Because of its low expression levels compared to ANP and BNP, early studies failed to show its existence and role in the heart. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with the distribution of its specific natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. NPR-B generates intracellular cyclic guanosine 3′,5′-monophosphate (cGMP) upon CNP binding, followed by various molecular effects including the activation of cGMP-dependent protein kinases, which generates diverse cytoprotective actions in cardiomyocytes, as well as in cardiac fibroblasts. CNP exerts negative inotropic and positive lusitropic responses in both normal and failing heart models. Furthermore, osteocrin, the intrinsic and specific ligand for the clearance receptor for natriuretic peptides, can augment the effects of CNP and may supply a novel therapeutic strategy for cardiac protection.
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9
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Meng F, Cheng H, Qian J, Dai X, Huang Y, Fan Y. In vitro fluidic systems: Applying shear stress on endothelial cells. MEDICINE IN NOVEL TECHNOLOGY AND DEVICES 2022. [DOI: 10.1016/j.medntd.2022.100143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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10
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Hu P, Chen H, Wang LH, Jiang JB, Li JM, Tang MY, Guo YC, Zhu QF, Pu ZX, Lin XP, Ng S, Liu XB, Wang JA. Elevated N-terminal pro C-type natriuretic peptide is associated with mortality in patients undergoing transcatheter aortic valve replacement. BMC Cardiovasc Disord 2022; 22:164. [PMID: 35413789 PMCID: PMC9004019 DOI: 10.1186/s12872-022-02615-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 04/01/2022] [Indexed: 12/02/2022] Open
Abstract
Background Unlike N-terminal pro-B-type natriuretic peptide (NT-proBNP), which have been extensively studied, little is known about the role of N-terminal pro-C-type natriuretic peptide (NT-proCNP) for predicting survival post transcatheter aortic valve replacement (TAVR). Methods A total of 309 patients were included in the analysis. Patients were grouped into quartiles (Q1–4) according to the baseline NT-proCNP value. Blood for NT-proCNP analysis was obtained prior to TAVR procedure. The primary endpoint was mortality after a median follow-up of 32 months. Multivariable Cox proportional hazards regression models analyzed prognostic factors. The predictive capability was compared between NT-proBNP and NT-proCNP using receiver operator curve (ROC) analysis. Results A total of 309 subjects with the mean age of 76.8 ± 6.3 years, among whom 58.6% were male, were included in the analysis. A total of 58 (18.8%) patients died during follow-up. Cox multivariable analyses indicated society of thoracic surgeons (STS)-score was a strong independent predictor for mortality (hazard ratio (HR) 1.08, 95% confidential interval (CI) 1.05–1.12, P < 0.001). Elevated NT-proCNP was associated with a higher risk of cardiovascular mortality (HR 1.02, 95% CI 1.00–1.03, P = 0.025) and All-cause mortality (HR 1.01, 95% CI 1.00–1.03, P = 0.027), whereas NT-proBNP showed a small effect size on mortality. ROC analysis indicated that NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with left ventricular ejection fraction (LVEF) < 50% [(Area under the curve (AUC)-values of 0.79 (0.69; 0.87) vs. 0.59 (0.48; 0.69), P = 0.0453]. Conclusions NT-proCNP and STS-Score were the independent prognostic factors of mortality among TAVR patients. Furthermore, NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with LVEF < 50%. Trial registration NCT02803294, 16/06/2016. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02615-8.
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Affiliation(s)
- Po Hu
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Han Chen
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Li-Han Wang
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Ju-Bo Jiang
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Jia-Min Li
- Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Meng-Yao Tang
- Renal Division, Brigham and Women's Hospital, Boston, MA, USA.,Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Yu-Chao Guo
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Qi-Feng Zhu
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Zhao-Xia Pu
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China.,Department of Echocardiography, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Xin-Ping Lin
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China.,Department of Echocardiography, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Stella Ng
- Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, 310009, Zhejiang, China
| | - Xian-Bao Liu
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. .,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
| | - Jian-An Wang
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. .,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
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11
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Ando J, Yamamoto K. Hemodynamic Forces, Endothelial Mechanotransduction, and Vascular Diseases. Magn Reson Med Sci 2022; 21:258-266. [PMID: 34024868 PMCID: PMC9680547 DOI: 10.2463/mrms.rev.2021-0018] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/23/2021] [Indexed: 11/09/2022] Open
Abstract
Cells in the tissues and organs of a living body are subjected to mechanical forces, such as pressure, friction, and tension from their surrounding environment. Cells are equipped with a mechanotransduction mechanism by which they perceive mechanical forces and transmit information into the cell interior, thereby causing physiological or pathogenetic mechano-responses. Endothelial cells (ECs) lining the inner surface of blood vessels are constantly exposed to shear stress caused by blood flow and a cyclic strain caused by intravascular pressure. A number of studies have shown that ECs are sensitive to changes in these hemodynamic forces and alter their morphology and function, sometimes by modifying gene expression. The mechanism of endothelial mechanotransduction has been elucidated, and the plasma membrane has recently been shown to act as a mechanosensor. The lipid order and cholesterol content of plasma membranes change immediately upon the exposure of ECs to hemodynamic forces, resulting in a change in membrane fluidity. These changes in a plasma membrane's physical properties affect the conformation and function of various ion channels, receptors, and microdomains (such as caveolae and primary cilia), thereby activating a wide variety of downstream signaling pathways. Such endothelial mechanotransduction works to maintain circulatory homeostasis; however, errors in endothelial mechanotransduction can cause abnormalities in vascular physiological function, leading to the initiation and progression of various vascular diseases, such as hypertension, thrombosis, aneurysms, and atherosclerosis. Recent advances in detailed imaging technology and computational fluid dynamics analysis have enabled us to evaluate the hemodynamic forces acting on vascular tissue accurately, contributing greatly to our understanding of vascular mechanotransduction and the pathogenesis of vascular diseases, as well as the development of new therapies for vascular diseases.
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Affiliation(s)
- Joji Ando
- Laboratory of Biomedical Engineering, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Kimiko Yamamoto
- Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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12
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Mark PD, Frydland M, Helgestad OKL, Holmvang L, Møller JE, Johansson PI, Ostrowski SR, Prickett T, Hassager C, Goetze JP. Sex-specific mortality prediction by pro-C-type natriuretic peptide measurement in a prospective cohort of patients with ST-elevation myocardial infarction. BMJ Open 2021; 11:e048312. [PMID: 34588247 PMCID: PMC8480007 DOI: 10.1136/bmjopen-2020-048312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE To determine the predictive value of pro-C-type natriuretic peptide (pro-CNP) measurement in plasma sampled on admission from patients presenting with ST-elevation myocardial infarction (STEMI). DESIGN Prospective cohort study. SETTING Two University Hospitals in Denmark. PARTICIPANTS 1760 consecutive patients (470 females and 1290 males) with confirmed STEMI. MAIN OUTCOMES AND MEASURES The main outcome was all-cause mortality at 1 year after presentation and the primary measure was pro-CNP concentration in plasma at admission in all patients and longitudinal measurements in a consecutive subgroup of 287 patients. A reference population (n=688) defined cut-off values of increased pro-CNP concentrations. RESULTS In all patients, an increased pro-CNP concentration was associated with a higher all-cause mortality after 1 year (HR 1.6, 95% CI 1.1 to 2.4, Plogrank=0.009) including an interaction of sex (p=0.03). In separate sex-stratified analyses, female patients showed increased all-cause mortality (HR1 year 2.6, 95% CI 1.5 to 4.6), Plogrank <0.001), whereas no differences were found in male patients (HR1 year 1.1, 95% CI 0.7 to 1.9, Plogrank=0.66). After adjusting for potential risk factors, we found increased pro-CNP concentrations≥the median value to be independently associated with increased risk of mortality in female patients within 1 year (HR per 1 pmol/L increase: 1.04, 95% CI 1.01 to 1.06, p=0.007). Moreover, we found indications of sex differences in pro-CNP concentrations over time (higher pro-CNP in males (4.4, 95% CI -0.28 to 9.1 pmol/L, p=0.07) and interaction of sex and time (p=0.13)), and that hypertension was independently associated with higher pro-CNP (4.5, 95% CI 0.6 to 8.4 pmol/L, p=0.03). CONCLUSIONS In female but not male patients presenting with STEMI, high concentrations of pro-CNP (≥median) at admission independently indicate a higher risk of all-cause mortality. The findings are remarkably specific for female patients, suggesting a different vascular phenotype beyond traditional measures of coronary artery flow compared with male patients.
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Affiliation(s)
- Peter D Mark
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Martin Frydland
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | | | - Lene Holmvang
- Department of Cardiology, Odense University hospital, Odense, Denmark
| | | | - Pär I Johansson
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Sisse R Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Timothy Prickett
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Christian Hassager
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Jens Peter Goetze
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Denmark
- Department of Biomedical Sciences, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark
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13
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Hosoki S, Tanaka T, Ihara M. Diagnostic and prognostic blood biomarkers in vascular dementia: From the viewpoint of ischemic stroke. Neurochem Int 2021; 146:105015. [PMID: 33781849 DOI: 10.1016/j.neuint.2021.105015] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
Reliable quantitative blood biomarkers are important in vascular dementia (VaD) because early diagnosis and therapeutic intervention are effective in preventing progression of dementia. Although many blood biomarkers for acute ischemic stroke (AIS) or VaD have been reported, there are few reliable blood biomarkers. VaD and AIS have similar pathological conditions that are associated with small vessel disease (SVD) such as oxidative stress, inflammation, endothelial dysfunction, and neuronal injury. Therefore, it may be possible to find superior blood biomarkers of VaD among AIS blood biomarkers. Owing to recent developments, noncoding RNAs such as microRNA and long noncoding RNA, which can be analyzed using a single drop of blood, are also particularly reliable VaD markers because they stably reflect brain tissue damage. A multimarker combining several blood biomarkers or artificial intelligence technology may also be beneficial to compensate for insufficiencies of a single blood biomarker. This review describes the blood biomarkers of VaD and how they are related to blood biomarkers of AIS.
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Affiliation(s)
- Satoshi Hosoki
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Tomotaka Tanaka
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
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14
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Hirata T, Yamamoto K, Ikeda K, Arita M. Functional lipidomics of vascular endothelial cells in response to laminar shear stress. FASEB J 2021; 35:e21301. [PMID: 33421194 DOI: 10.1096/fj.202002144r] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 12/03/2020] [Accepted: 12/08/2020] [Indexed: 11/11/2022]
Abstract
Laminar shear stress generated by blood flow stimulates endothelial cells and activates signal transduction, which plays an important role in vascular homeostasis. Several lines of evidence indicate that membrane and intracellular lipids are involved in the signal transduction of biomechanical stresses. In this study, we performed global profiling of cellular lipids from human pulmonary artery endothelial cells (HPAEC) exposed to laminar shear stress. A total of 761 species of lipids were successfully annotated, with 198 of these species significantly changed in response to shear stress for 24 hours. Ether-linked lipids containing an alkyl moiety with a medium chain length (C11-C14) were uniquely upregulated, and the administration of their biosynthetic precursor 1-O-dodecyl-rac-glycerol attenuated phorbol 12-myristate 13-acetate (PMA) induced vascular cell adhesion molecule-1 (VCAM-1) expression. Given the pro-inflammatory and atherogenic roles of VCAM-1, our findings suggest that the induction of a specific group of lipids (ie, ether-linked lipids with medium length alkyl side chain) may confer atheroprotective and anti-inflammatory roles to vascular endothelial cells under flow conditions.
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Affiliation(s)
- Tsuyoshi Hirata
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.,Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
| | - Kimiko Yamamoto
- Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kazutaka Ikeda
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.,Laboratory of Biomolecule Analysis, Kazusa DNA Research Institute, Japan
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.,Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.,Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan
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15
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Nakayama A, Albarrán-Juárez J, Liang G, Roquid KA, Iring A, Tonack S, Chen M, Müller OJ, Weinstein LS, Offermanns S. Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis. JCI Insight 2020; 5:140485. [PMID: 33268595 PMCID: PMC7714404 DOI: 10.1172/jci.insight.140485] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/28/2020] [Indexed: 01/05/2023] Open
Abstract
Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor–like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow–induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis. Disturbed flow promotes the release of adrenomedullin from endothelial cells and activates Gs-mediated signaling, which reduces endothelial inflammation in vitro and in vivo.
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Affiliation(s)
- Akiko Nakayama
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Julián Albarrán-Juárez
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Guozheng Liang
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Kenneth Anthony Roquid
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - András Iring
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Sarah Tonack
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Min Chen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Oliver J Müller
- Department of Internal Medicine III, University of Kiel, Kiel, and German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Kiel/Lübeck, Germany
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Stefan Offermanns
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany.,Centre for Molecular Medicine, Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany.,DZHK RheinMain, Germany
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16
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Abstract
Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
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17
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Prickett TC, A Espiner E. Circulating products of C-type natriuretic peptide and links with organ function in health and disease. Peptides 2020; 132:170363. [PMID: 32634451 DOI: 10.1016/j.peptides.2020.170363] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/08/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023]
Abstract
Paracrine actions of CNP and rapid degradation at source severely limit study of CNP's many roles in vivo. However provided sensitive and validated assays are used, there is increasing evidence that low concentrations of bioactive CNP in plasma, and the readily detectable concentrations of the bio-inactive processed product of proCNP (aminoterminal proCNP), can be used to advance understanding of the hormone's role in pathophysiology. Provided renal function is normal, concordant changes in both CNP and NTproCNP reflect change in tissue production of proCNP whereas change in CNP alone results from altered rates of bioactive CNP degradation and are reflected in the ratio of NTproCNP to CNP. As already shown in juveniles, where plasma concentration of CNP products are higher and are associated with concurrent endochondral bone growth, measurements of plasma CNP products in mature adults have potential to clarify organ response to stress and injury. Excepting the role of CNP in fetal-maternal welfare, this review examines evidence linking plasma CNP products with function of a wide range of tissues in adults, including the impact of extraneous factors such as nutrients, hormone therapy and exercise.
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Affiliation(s)
- Timothy Cr Prickett
- Department of Medicine, University of Otago, PO Box 4345, Christchurch, 8140 New Zealand.
| | - Eric A Espiner
- Department of Medicine, University of Otago, PO Box 4345, Christchurch, 8140 New Zealand
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18
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Caprnda M, Zulli A, Shiwani HA, Kubatka P, Filipova S, Valentova V, Gazdikova K, Mozos I, Berukstis A, Laucevicius A, Rihacek I, Dragasek J, Prosecky R, Egom EE, Staffa R, Kruzliak P, Krasnik V. The therapeutic effect of B-type natriuretic peptides in acute decompensated heart failure. Clin Exp Pharmacol Physiol 2020; 47:1120-1133. [PMID: 32083749 DOI: 10.1111/1440-1681.13290] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/03/2020] [Accepted: 02/19/2020] [Indexed: 12/23/2022]
Abstract
B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.
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Affiliation(s)
- Martin Caprnda
- First Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Haaris A Shiwani
- Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Trust, Lancaster, UK
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Division of Oncology, Department of Experimental Carcinogenesis, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Slavomira Filipova
- Department of Cardiology, National Institute of Cardiovascular Diseases and Slovak Medical University, Bratislava, Slovakia
| | - Vanda Valentova
- Division of Oncology, Department of Experimental Carcinogenesis, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Independent Researcher, Mosjøen, Norway
| | - Katarina Gazdikova
- Department of Nutrition, Faculty of Nursing and Professional Health Studies, Slovak Medical University, Bratislava, Slovakia
- Department of General Medicine, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia
| | - Ioana Mozos
- Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
- Center for Translational Research and Systems Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Andrius Berukstis
- Clinic of Heart and Vessel Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Aleksandras Laucevicius
- Clinic of Heart and Vessel Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ivan Rihacek
- Second Department of Internal Medicine, Faculty of Medicine, Masaryk University and St, Anne´s University Hospital, Brno, Czech Republic
| | - Jozef Dragasek
- First Department of Psychiatry, Faculty of Medicine, Luis Pasteur University Hospital, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Robert Prosecky
- Department of Internal Medicine, Brothers of Mercy Hospital, Brno, Czech Republic
| | - Emmanuel E Egom
- Egom Clinical & Translational Research Services Ltd, Dartmouth, NS, Canada
- Jewish General Hospital and Lady Davis Research Institute, Montreal, QC, Canada
| | - Robert Staffa
- Second Department of Surgery, Faculty of Medicine, St. Anne´s University Hospital, Masaryk University, Brno, Czech Republic
| | - Peter Kruzliak
- Department of Internal Medicine, Brothers of Mercy Hospital, Brno, Czech Republic
- Second Department of Surgery, Faculty of Medicine, St. Anne´s University Hospital, Masaryk University, Brno, Czech Republic
| | - Vladimir Krasnik
- Department of Ophthalmology, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
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19
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Effect of statin therapy on plasma C-type Natriuretic Peptides and Endothelin-1 in males with and without symptomatic coronary artery disease. Sci Rep 2020; 10:7927. [PMID: 32404888 PMCID: PMC7220949 DOI: 10.1038/s41598-020-64795-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/17/2020] [Indexed: 12/18/2022] Open
Abstract
C-type Natriuretic Peptide (CNP) and Endothelin-1 (ET-1) have reciprocal roles in maintaining vascular homeostasis and are acutely modulated by statins in human cultured endothelial cells. Whether these actions of statins in vitro are reflected in studies in vivo is unknown. In a prospective study of 66 subjects with or without post- acute coronary syndrome (ACS), plasma concentrations of bioactive CNP and bio-inactive aminoterminal proCNP (NTproCNP), ET-1, B-type Natriuretic Peptide (BNP) and high sensitivity C Reactive Protein (hsCRP) were measured together with lipids before and at intervals of 1, 2 and 7 days after commencing atorvastatin 40 mg/day - and for a further period of 6months in those with ACS. Plasma lipids fell significantly in all subjects but plasma CNP, NTproCNP and ET-1 were unchanged by atorvastatin. In ACS, baseline hsCRP, BNP and CNP but not NTproCNP or ET-1 were significantly raised compared to values in age-matched controls. The ratio of NTproCNP to CNP was significantly lower in ACS throughout the study and was unaffected by statin therapy. We conclude that conventional doses of atorvastatin do not affect plasma CNP products or ET-1. Elevated CNP after cardiac injury likely results from regulated changes in clearance, not enhanced production.
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20
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Taura D, Nakao K, Nakagawa Y, Kinoshita H, Sone M, Nakao K. C-type natriuretic peptide (CNP)/guanylate cyclase B (GC-B) system and endothelin-1(ET-1)/ET receptor A and B system in human vasculature. Can J Physiol Pharmacol 2020; 98:611-617. [PMID: 32268070 DOI: 10.1139/cjpp-2019-0686] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
To assess the physiological and clinical implications of the C-type natriuretic peptide (CNP)/guanylyl cyclase B (GC-B) system in the human vasculature, we have examined gene expressions of CNP and its receptor, GC-B, in human vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and have also compared the endothelin-1(ET-1)/endothelin receptor-A (ETR-A) and endothelin receptor-B (ETR-B) system in human aortic ECs (HAECs) and vascular SMCs (HSMCs) in vitro. We also examined these gene expressions in human embryonic stem (ES)/induced pluripotent stem cell (iPS)-derived ECs and mural cells (MCs). A little but significant amount of mRNA encoding CNP was detected in both human ES-derived ECs and HAECs. A substantial amount of GC-B was expressed in both ECs (iPS-derived ECs and HAECs) and SMCs (iPS-derived MCs and HSMCs). ET-1 was expressed solely in ECs. ETR-A was expressed in SMCs, while ETR-B was expressed in ECs. These results indicate the existence of a vascular CNP/GC-B system in the human vascular wall, indicating the evidence for clinical implication of the CNP/GC-B system in concert with the ET-1/ETR-A and ETR-B system in the human vasculature.
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Affiliation(s)
- Daisuke Taura
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuhiro Nakao
- National Cardiovascular, Cerebrovascular Research Center Hospital, Suita, Japan
| | - Yasuaki Nakagawa
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hideyuki Kinoshita
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masakatsu Sone
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuwa Nakao
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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21
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Ichimura M, Sasaki S, Ogino T. Tapping enhances vasodilation for venipuncture even in individuals with veins that are relatively difficult to palpate. Clin Anat 2020; 33:440-445. [PMID: 31908028 DOI: 10.1002/ca.23559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 01/03/2020] [Indexed: 11/06/2022]
Abstract
INTRODUCTION This study evaluated whether tapping enhances vasodilation in individuals with veins that are relatively difficult to palpate. MATERIALS AND METHODS Twenty participants (4 men and 16 women, aged 19-22 years) with cutaneous veins that were relatively difficult to palpate even after tourniquet application were recruited. A crossover trial with/without tapping (10 times in 5 s) was performed under tourniquet inflation on the upper arm. Vasodilation was evaluated by venous cross-sectional area, depth of the vein, and elevation of the overlying skin by ultrasonography. Venous palpation scores were also measured. The degree of improvement was estimated by simulation. RESULTS In total, 60% of participants "sometimes" or "often" experienced unsuccessful venipuncture. After the tapping procedure, the venous cross-sectional area significantly increased (14.6 ± 9.12 mm2 for control and 15.2 ± 9.79 mm2 for tapping) and venous depth significantly decreased (4.57 ± 2.31 mm for control and 4.23 ± 2.41 mm for tapping). A simulation study using these values suggested that tapping increased the longitudinal and crosswise successful ranges of venipuncture by 5-6%. CONCLUSIONS Tapping in this study enhanced the vasodilation of cutaneous veins that are relatively difficult to palpate. The effectiveness of various vasodilation methods may be compared through the estimation of improvement.
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Affiliation(s)
- Mika Ichimura
- Department of Nursing, Faculty of Health Sciences and Welfare, Kibi International University, Takahashi, Okayama, Japan
| | - Shinsuke Sasaki
- Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Okayama, Japan
| | - Tetsuya Ogino
- Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Okayama, Japan
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22
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de Roij van Zuijdewijn CLM, van Gastel LHA, Ter Wee PM, Bots ML, Blankestijn PJ, van den Dorpel MA, Fouque D, Nubé MJ, Grooteman MPC. The effect of natriuretic C-type peptide and its change over time on mortality in patients on haemodialysis or haemodiafiltration. Clin Kidney J 2019; 14:375-381. [PMID: 33564441 PMCID: PMC7857796 DOI: 10.1093/ckj/sfz156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/01/2019] [Indexed: 11/12/2022] Open
Abstract
Background C-type natriuretic peptide (CNP) and its co-product N-terminal proCNP (NTproCNP) have been associated with beneficial effects on the cardiovascular system. In prevalent dialysis patients, however, a relation between NTproCNP and mortality has not yet been investigated. Furthermore, as a middle molecular weight substance, its concentration might be influenced by dialysis modality. Methods In a cohort of patients treated with haemodialysis (HD) or haemodiafiltration (HDF), levels of NTproCNP were measured at baseline and 6, 12, 24 and 36 months. The relation between serum NTproCNP and mortality and the relation between the 6-month rate of change of NTproCNP and mortality were analysed using Cox regression models. For the longitudinal analyses, linear mixed models were used. Results In total, 406 subjects were studied. The median baseline serum NTproCNP was 93 pmol/L and the median follow-up was 2.97 years. No relation between baseline NTproCNP or its rate of change over 6 months and mortality was found. NTproCNP levels remained stable in HD patients, whereas NTproCNP decreased significantly in HDF patients. The relative decline depended on the magnitude of the convection volume. Conclusions In our study, levels of NTproCNP appear strongly elevated in prevalent dialysis patients. Second, while NTproCNP remains unaltered in HD patients, its levels decline in individuals treated with HDF, with the decline dependent on the magnitude of the convection volume. Third, NTproCNP is not related to mortality in this population. Thus NTproCNP does not seem to be a useful marker for mortality risk in dialysis patients.
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Affiliation(s)
- Camiel L M de Roij van Zuijdewijn
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Lieke H A van Gastel
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Piet M Ter Wee
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Michiel L Bots
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Peter J Blankestijn
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Denis Fouque
- Centre Hospitalier Universitaire de Lyon, Pierre Benite, France
| | - Menso J Nubé
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Muriel P C Grooteman
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Oatmen KE, Zile MR, Burnett JC, Spinale FG. Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure: A Review. JAMA Cardiol 2019; 3:1232-1243. [PMID: 30484834 DOI: 10.1001/jamacardio.2018.3789] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Importance The standard pharmacotherapy for heart failure (HF), particularly HF with reduced ejection fraction (HFrEF), is primarily through the use of receptor antagonists, notably inhibition of the renin-angiotensin system by either angiotensin-converting enzyme inhibition or angiotensin II receptor blockade (ARB). However, the completed Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial identified that the use of a single molecule (sacubitril/valsartan), which is an ARB and the neutral endopeptidase inhibitor (NEPi) neprilysin, yielded improved clinical outcomes in HFrEF compared with angiotensin-converting enzyme inhibition alone. Observations This review examined specific bioactive signaling pathways that would be potentiated by NEPi and how these would affect key cardiovascular processes relevant to HFrEF. It also addressed potential additive/synergistic effects of ARB. A number of biological signaling pathways that may be potentiated by sacubitril/valsartan were identified, including some novel candidate molecules, which will act in a synergistic manner to favorably alter the natural history of HFrEF. Conclusions and Relevance This review identified that activation rather than inhibition of specific receptor pathways provided favorable cardiovascular effects that cannot be achieved by renin-angiotensin system inhibition alone. Thus, an entirely new avenue of translational and clinical research lies ahead in which HF pharmacotherapies will move beyond receptor antagonist strategies.
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Affiliation(s)
- Kelsie E Oatmen
- Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia
| | - Michael R Zile
- Medical University of South Carolina, Charleston.,Ralph H. Johnson Department of VA Medical Center, Charleston, South Carolina
| | - John C Burnett
- Cardiorenal Research Laboratory, Mayo Clinic, Rochester, Minnesota
| | - Francis G Spinale
- Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia.,William Jennings Bryan Dorn VA Medical Center, Columbia, South Carolina
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24
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Prickett TCR, Spittlehouse JK, Miller AL, Liau Y, Kennedy MA, Cameron VA, Pearson JF, Boden JM, Troughton RW, Espiner EA. Contrasting signals of cardiovascular health among natriuretic peptides in subjects without heart disease. Sci Rep 2019; 9:12108. [PMID: 31431677 PMCID: PMC6702214 DOI: 10.1038/s41598-019-48553-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/07/2019] [Indexed: 01/22/2023] Open
Abstract
Natriuretic Peptides (NP) are important in maintaining normal cardiac and metabolic status and have been used to predict cardiovascular events. Whether plasma concentrations of NP products within the normal range reflect cardio-metabolic health is unknown. Plasma NTproANP, NTproBNP and NTproCNP and their bioactive counterparts were measured in a random sample of 348 community dwellers aged 49-51 yr without heart disease and associations sought with established vascular risk factors, echocardiographic indices and a genetic variant previously linked with BNP. Stratified by sex, each of ten vascular risk factors were positively associated with NTproCNP whereas associations with NTproBNP and NTproANP were all negative. In both sexes, higher plasma NTproCNP was associated with higher arterial elastance, lower LV stroke volume and lower LV end diastolic volume. Exactly opposite associations were found with plasma NTproBNP or NTproANP. Sex specific differences were identified: positive association of NTproBNP with LV end systolic volume and the negative association with LV elastance were found only in males. The genetic variant rs198358 was independently associated with NTproBNP but not with NTproANP. In conclusion, higher NTproCNP is likely to be an adaptive response to impaired LV relaxation whereas genetic factors likely contribute to higher NTproBNP and improved cardio-metabolic health at midlife.
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Affiliation(s)
| | | | - Allison L Miller
- Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Yusmiati Liau
- Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Martin A Kennedy
- Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Vicky A Cameron
- Departments of Medicine, University of Otago, Christchurch, New Zealand
| | - John F Pearson
- Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
- Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
| | - Joseph M Boden
- Psychological Medicine, University of Otago, Christchurch, New Zealand
| | | | - Eric A Espiner
- Departments of Medicine, University of Otago, Christchurch, New Zealand
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25
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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: 145] [Impact Index Per Article: 24.2] [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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26
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Hofmann F. A concise discussion of the regulatory role of cGMP kinase I in cardiac physiology and pathology. Basic Res Cardiol 2018; 113:31. [PMID: 29934662 DOI: 10.1007/s00395-018-0690-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 05/18/2018] [Accepted: 06/13/2018] [Indexed: 12/25/2022]
Abstract
The underlying cause of cardiac hypertrophy, fibrosis, and heart failure has been investigated in great detail using different mouse models. These studies indicated that cGMP and cGMP-dependent protein kinase type I (cGKI) may ameliorate these negative phenotypes in the adult heart. Recently, evidence has been published that cardiac mitochondrial BKCa channels are a target for cGKI and that activation of mitoBKCa channels may cause some of the positive effects of conditioning in ischemia/reperfusion injury. It will be pointed out that most studies could not present convincing evidence that it is the cGMP level and the activity cGKI in specific cardiac cells that reduces hypertrophy or heart failure. However, anti-fibrotic compounds stimulating nitric oxide-sensitive guanylyl cyclase may be an upcoming therapy for abnormal cardiac remodeling.
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Affiliation(s)
- Franz Hofmann
- Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802, Munich, Germany.
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27
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Abstract
Natriuretic peptides are structurally related, functionally diverse hormones. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are delivered predominantly by the heart. Two C-type natriuretic peptides (CNPs) are paracrine messengers, notably in bone, brain, and vessels. Natriuretic peptides act by binding to the extracellular domains of three receptors, NPR-A, NPR-B, and NPR-C of which the first two are guanylate cyclases. NPR-C is coupled to inhibitory proteins. Atrial wall stress is the major regulator of ANP secretion; however, atrial pressure changes plasma ANP only modestly and transiently, and the relation between plasma ANP and atrial wall tension (or extracellular volume or sodium intake) is weak. Absence and overexpression of ANP-related genes are associated with modest blood pressure changes. ANP augments vascular permeability and reduces vascular contractility, renin and aldosterone secretion, sympathetic nerve activity, and renal tubular sodium transport. Within the physiological range of plasma ANP, the responses to step-up changes are unimpressive; in man, the systemic physiological effects include diminution of renin secretion, aldosterone secretion, and cardiac preload. For BNP, the available evidence does not show that cardiac release to the blood is related to sodium homeostasis or body fluid control. CNPs are not circulating hormones, but primarily paracrine messengers important to ossification, nervous system development, and endothelial function. Normally, natriuretic peptides are not powerful natriuretic/diuretic hormones; common conclusions are not consistently supported by hard data. ANP may provide fine-tuning of reno-cardiovascular relationships, but seems, together with BNP, primarily involved in the regulation of cardiac performance and remodeling. © 2017 American Physiological Society. Compr Physiol 8:1211-1249, 2018.
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Affiliation(s)
- Peter Bie
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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28
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Yang R, Broussard JA, Green KJ, Espinosa HD. Techniques to stimulate and interrogate cell-cell adhesion mechanics. EXTREME MECHANICS LETTERS 2018; 20:125-139. [PMID: 30320194 PMCID: PMC6181239 DOI: 10.1016/j.eml.2017.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cell-cell adhesions maintain the mechanical integrity of multicellular tissues and have recently been found to act as mechanotransducers, translating mechanical cues into biochemical signals. Mechanotransduction studies have primarily focused on focal adhesions, sites of cell-substrate attachment. These studies leverage technical advances in devices and systems interfacing with living cells through cell-extracellular matrix adhesions. As reports of aberrant signal transduction originating from mutations in cell-cell adhesion molecules are being increasingly associated with disease states, growing attention is being paid to this intercellular signaling hub. Along with this renewed focus, new requirements arise for the interrogation and stimulation of cell-cell adhesive junctions. This review covers established experimental techniques for stimulation and interrogation of cell-cell adhesion from cell pairs to monolayers.
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Affiliation(s)
- Ruiguo Yang
- Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, United States
- Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, United States
| | - Joshua A. Broussard
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Kathleen J. Green
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States
- Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Horacio D. Espinosa
- Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
- Theoretical and Applied Mechanics Program, Northwestern University, Evanston, IL 60208, United States
- Institute for Cellular Engineering Technologies, Northwestern University, Evanston, IL 60208, United States
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29
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Braun K, Oeckl J, Westermeier J, Li Y, Klingenspor M. Non-adrenergic control of lipolysis and thermogenesis in adipose tissues. ACTA ACUST UNITED AC 2018. [PMID: 29514884 DOI: 10.1242/jeb.165381] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy balance, lipolysis of triacylglycerols and re-esterification of free fatty acids are opposing processes operating in parallel at identical rates, thus allowing a more dynamic transition from anabolism to catabolism, and vice versa. In response to alterations in the state of energy balance, one of the two processes predominates, enabling the efficient mobilization or storage of energy in a negative or positive energy balance, respectively. The release of noradrenaline from the sympathetic nervous system activates lipolysis in a depot-specific manner by initiating the canonical adrenergic receptor-Gs-protein-adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A pathway, targeting proteins of the lipolytic machinery associated with the interface of the lipid droplets. In brown and brite adipocytes, lipolysis stimulated by this signaling pathway is a prerequisite for the activation of non-shivering thermogenesis. Free fatty acids released by lipolysis are direct activators of uncoupling protein 1-mediated leak respiration. Thus, pro- and anti-lipolytic mediators are bona fide modulators of thermogenesis in brown and brite adipocytes. In this Review, we discuss adrenergic and non-adrenergic mechanisms controlling lipolysis and thermogenesis and provide a comprehensive overview of pro- and anti-lipolytic mediators.
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Affiliation(s)
- Katharina Braun
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,ZIEL - Institute for Food & Health, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
| | - Josef Oeckl
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,ZIEL - Institute for Food & Health, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
| | - Julia Westermeier
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
| | - Yongguo Li
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany .,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany.,ZIEL - Institute for Food & Health, Technical University of Munich, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
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30
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Wang L, Liu W, Yu Y, Jiang L, Yang J. Increased circulating bioactive C-type natriuretic peptide is associated with reduced heart rate variability in patients with chronic kidney disease. BMC Nephrol 2018; 19:50. [PMID: 29506482 PMCID: PMC5839007 DOI: 10.1186/s12882-018-0843-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 02/19/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD. METHODS Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity. RESULTS Mean (±standard deviation) age of the patients were 59.9 (±14.9) years and 56.6% were male. Average plasma CNP level was 790.8 ± 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction (with vs. without endothelial dysfunction: 844.6 ± 365.5 pg/ml vs. 738.3 ± 231.8 pg/ml, p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters (SDNN, RMSSD, Triangular Index). The association of CNP with HRV persisted after adjustment for potential covariates. CONCLUSIONS Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients.
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Affiliation(s)
- Lulu Wang
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, 262# North Zhongshan Road, Nanjing, 210003, China
| | - Wenjin Liu
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, 262# North Zhongshan Road, Nanjing, 210003, China
| | - Yanting Yu
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, 262# North Zhongshan Road, Nanjing, 210003, China.,Departments of nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Lei Jiang
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, 262# North Zhongshan Road, Nanjing, 210003, China.
| | - Junwei Yang
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, 262# North Zhongshan Road, Nanjing, 210003, China.
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31
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Di Nicolò P. The dark side of the kidney in cardio-renal syndrome: renal venous hypertension and congestive kidney failure. Heart Fail Rev 2018; 23:291-302. [DOI: 10.1007/s10741-018-9673-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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32
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Kim J, Mirando AC, Popel AS, Green JJ. Gene delivery nanoparticles to modulate angiogenesis. Adv Drug Deliv Rev 2017; 119:20-43. [PMID: 27913120 PMCID: PMC5449271 DOI: 10.1016/j.addr.2016.11.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 10/01/2016] [Accepted: 11/24/2016] [Indexed: 01/19/2023]
Abstract
Angiogenesis is naturally balanced by many pro- and anti-angiogenic factors while an imbalance of these factors leads to aberrant angiogenesis, which is closely associated with many diseases. Gene therapy has become a promising strategy for the treatment of such a disordered state through the introduction of exogenous nucleic acids that express or silence the target agents, thereby engineering neovascularization in both directions. Numerous non-viral gene delivery nanoparticles have been investigated towards this goal, but their clinical translation has been hampered by issues associated with safety, delivery efficiency, and therapeutic effect. This review summarizes key factors targeted for therapeutic angiogenesis and anti-angiogenesis gene therapy, non-viral nanoparticle-mediated approaches to gene delivery, and recent gene therapy applications in pre-clinical and clinical trials for ischemia, tissue regeneration, cancer, and wet age-related macular degeneration. Enhanced nanoparticle design strategies are also proposed to further improve the efficacy of gene delivery nanoparticles to modulate angiogenesis.
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Affiliation(s)
- Jayoung Kim
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Adam C Mirando
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Jordan J Green
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Departments of Ophthalmology, Neurosurgery, and Materials Science & Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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33
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Acosta S, Gottsäter A, Engström G, Melander O, Zarrouk M, Nilsson PM, Smith JG. Circulating Midregional Proadrenomedullin and Risk of Incident Abdominal Aortic Aneurysm: A Prospective Longitudinal Cohort Study. Angiology 2017; 69:333-338. [PMID: 28766358 DOI: 10.1177/0003319717723255] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Prospective clinical plasma biomarker studies in abdominal aortic aneurysm (AAA) pathogenesis have been hampered by the need for very large cohorts and long follow-up time. The main aim of the present study was to evaluate the association of adrenomedullin, a cardiovascular (CV) stress marker, and incident AAA risk. Prospective longitudinal cohort of middle-aged individuals from the CV cohort of the Malmö Diet and Cancer Study (n = 5551; 1991-1994) was assessed. Plasma concentrations of midregional proadrenomedullin (MR-proADM), C-reactive protein (CRP), and conventional risk factors were measured at baseline. Incidence of AAA was studied up to December 31, 2013. Cumulative incidence of AAA was 1.5% (men 2.9%, women 0.5%). Mean age of individuals with incident AAA was 59.7 years at study entry, and AAA was diagnosed on average 14 years later. Adjusting for age, gender, smoking, body mass index, hypertension, diabetes mellitus, and CRP, MR-proADM (hazard ratio: 1.28; 95% confidence interval: 1.01-1.62) was independently associated with incident AAA. The plasma biomarker MR-proADM seems to be a marker of AAA risk, implying that AAA development may be driven by long-standing CV stress on the aortic wall.
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Affiliation(s)
- Stefan Acosta
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.,2 Department of Cardiothoracic and Vascular Surgery, Vascular Centre, Skåne University Hospital, Malmö, Sweden
| | - Anders Gottsäter
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.,2 Department of Cardiothoracic and Vascular Surgery, Vascular Centre, Skåne University Hospital, Malmö, Sweden
| | - Gunnar Engström
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Olle Melander
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.,3 Department of Internal Medicine and Emergency Medicine, Skåne University Hospital, Malmö, Sweden
| | - Moncef Zarrouk
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.,2 Department of Cardiothoracic and Vascular Surgery, Vascular Centre, Skåne University Hospital, Malmö, Sweden
| | - Peter M Nilsson
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - J Gustav Smith
- 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.,4 Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden
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34
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Pervez MO, Lyngbakken MN, Myhre PL, Brynildsen J, Langsjøen EC, Høiseth AD, Christensen G, Omland T, Røsjø H. Mid-regional pro-adrenomedullin in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study. Clin Biochem 2017; 50:394-400. [DOI: 10.1016/j.clinbiochem.2016.12.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/24/2016] [Accepted: 12/27/2016] [Indexed: 12/28/2022]
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35
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Rignault-Clerc S, Bielmann C, Liaudet L, Waeber B, Feihl F, Rosenblatt-Velin N. Natriuretic Peptide Receptor B modulates the proliferation of the cardiac cells expressing the Stem Cell Antigen-1. Sci Rep 2017; 7:41936. [PMID: 28181511 PMCID: PMC5299447 DOI: 10.1038/srep41936] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 01/04/2017] [Indexed: 12/21/2022] Open
Abstract
Brain Natriuretic Peptide (BNP) injections in adult “healthy” or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1+ cell proliferation. The Sca-1+ cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1+ cells expressing Nkx2.5, in Sca-1+ cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1+ cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1+ cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1+ cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated.
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Affiliation(s)
- Stéphanie Rignault-Clerc
- Unité de Physiopathologie Clinique Centre Hospitalier Universitaire Vaudois and University of Lausanne, Bugnon 7a, 1005 Lausanne, Switzerland
| | - Christelle Bielmann
- Unité de Physiopathologie Clinique Centre Hospitalier Universitaire Vaudois and University of Lausanne, Bugnon 7a, 1005 Lausanne, Switzerland
| | - Lucas Liaudet
- Service de Médecine Intensive Adulte, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
| | - Bernard Waeber
- Unité de Physiopathologie Clinique Centre Hospitalier Universitaire Vaudois and University of Lausanne, Bugnon 7a, 1005 Lausanne, Switzerland
| | - François Feihl
- Unité de Physiopathologie Clinique Centre Hospitalier Universitaire Vaudois and University of Lausanne, Bugnon 7a, 1005 Lausanne, Switzerland
| | - Nathalie Rosenblatt-Velin
- Unité de Physiopathologie Clinique Centre Hospitalier Universitaire Vaudois and University of Lausanne, Bugnon 7a, 1005 Lausanne, Switzerland
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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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Charitakis E, Walfridsson H, Nylander E, Alehagen U. Neurohormonal Activation After Atrial Fibrillation Initiation in Patients Eligible for Catheter Ablation: A Randomized Controlled Study. J Am Heart Assoc 2016; 5:e003957. [PMID: 27956398 PMCID: PMC5210434 DOI: 10.1161/jaha.116.003957] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 11/08/2016] [Indexed: 11/18/2022]
Abstract
BACKGROUND Biomarker activation in atrial fibrillation (AF) has been widely studied, but the immediate effect of AF initiation remains unclear. We studied the effect of AF initiation on 2 cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the midregional fragment of the N-terminal of pro-atrial natriuretic peptide (MR-proANP), and 2 extracardiac biomarkers-the copeptin and the midregional portion of proadrenomedullin (MR-proADM). METHODS AND RESULTS This was a randomized controlled study, including 45 patients with AF who had been referred for radiofrequency ablation to the University Hospital, Linköping, Sweden, between February 2012 and April 2014. Freedom from AF during the 4 days prior to radiofrequency ablation was confirmed by transtelephonic ECGs. Biomarkers were collected from the femoral vein (fv), coronary sinus (CS), and left atrium (LA) prior to AF initiation (baseline) and 30 minutes later. The MR-proANP and NT-proBNP concentrations increased in the intervention group compared with the control group 30 minutes after the initiation of AF (MR-proANP: Pfv<0.001, PCS<0.001, PLA<0.001; NT-proBNP: PLA<0.001). Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF (Pfv=0.003, PCS=0.015, PLA=0.011). CONCLUSIONS AF is a strong stimulus that results in immediate activation of different biomarkers. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01553045.
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Affiliation(s)
- Emmanouil Charitakis
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Håkan Walfridsson
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Eva Nylander
- Department of Clinical Physiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Urban Alehagen
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
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Charitakis E, Walfridsson H, Alehagen U. Short-Term Influence of Radiofrequency Ablation on NT-proBNP, MR-proANP, Copeptin, and MR-proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study. J Am Heart Assoc 2016; 5:JAHA.116.003557. [PMID: 27633393 PMCID: PMC5079020 DOI: 10.1161/jaha.116.003557] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background There is limited knowledge on the short‐term influence of radiofrequency ablation (RFA) of atrial fibrillation (AF) on 2 cardiac biomarkers; the N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and the midregional fragment of the N‐terminal of pro‐ANP (MR‐proANP) and 2 extracardiac biomarkers; the c‐terminal provasopressin (copeptin) and the midregional portion of proadrenomedullin (MR‐proADM). There are also limited data concerning cardiac production of the latter two. Methods and Results We studied 192 consecutive patients eligible for RFA of AF referred to the University Hospital, Linköping, Sweden. NT‐proBNP, MR‐proANP, copeptin, and MR‐proADM levels were measured in peripheral blood, the coronary sinus (CS), and the left atrium before ablation, and in peripheral blood immediately and the day after RFA. The level of NT‐proBNP decreased the day after RFA in participants in AF at the time of RFA, compared to the participants in sinus rhythm who showed a slight increase (P<0.001). Furthermore, regardless of the actual rhythm, the level of MR‐proANP showed an increase immediately after RFA (P<0.001), followed by a decrease the day after ablation (P<0.001). Copeptin level showed a 6‐fold increase immediately after RFA compared to baseline (P<0.001), whereas MR‐proADM level increased the day after RFA (P<0.001). Levels of copeptin and MR‐proADM were not higher in the CS compared to peripheral blood. Conclusions RFA of AF is a strong stimulus with a significant and direct impact on different neurohormonal systems. We found no sign of a cardiac release of MR‐proADM or copeptin. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01553045.
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Affiliation(s)
- Emmanouil Charitakis
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Håkan Walfridsson
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Urban Alehagen
- Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
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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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Abstract
cGMP controls many cellular functions ranging from growth, viability, and differentiation to contractility, secretion, and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains. These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular COOH-terminal catalytic (cGMP synthesizing) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptide, stimulating endochondral ossification in autocrine way. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina, and their activation by intracellular Ca(2+)-regulated proteins is essential for vision. Finally, in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO2and by peptidergic (guanylins) and nonpeptidergic odorants as well as by coolness, which has implications for social behaviors. In the past years advances in human and mouse genetics as well as the development of sensitive biosensors monitoring the spatiotemporal dynamics of cGMP in living cells have provided novel relevant information about this receptor family. This increased our understanding of the mechanisms of signal transduction, regulation, and (dys)function of the membrane GCs, clarified their relevance for genetic and acquired diseases and, importantly, has revealed novel targets for therapies. The present review aims to illustrate these different features of membrane GCs and the main open questions in this field.
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Affiliation(s)
- Michaela Kuhn
- Institute of Physiology, University of Würzburg, Würzburg, Germany
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Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling. Cell Signal 2015; 28:741-8. [PMID: 26658094 DOI: 10.1016/j.cellsig.2015.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/27/2015] [Accepted: 12/01/2015] [Indexed: 11/20/2022]
Abstract
Although cAMP-signalling regulates numerous functions of vascular endothelial cells (VECs), including their ability to impact vascular resistance in response to changes in blood flow dynamics, few of the mechanisms underlying these effects have yet to be described. In addition to forming stable adherens junctions (AJs) in static VEC cultures, VE-cadherin (VECAD) has emerged as a critical component in a key mechanosensor responsible for linking altered blood flow dynamics and the VEC-mediated control of vascular resistance. Previously, a cAMP phosphodiesterase, PDE4D, was shown to coordinate the VEC permeability limiting effects of cAMP-elevating agents in human arterial VECs (HAECs). Herein, we report that PDE4D acts to allow cAMP-elevating agents to regulate VECADs' role as a sensor of flow-associated fluid shear stress (FSS)-encoded information in HAECs. Thus, we report that PDE4 activity is increased in HAECs exposed to laminar FSS and that this effect contributes to controlling how FSS impacts the morphological and gene expression changes in HAECs exposed to flow. More specifically, we report that PDE4D regulates the efficiency with which VECAD, within its mechanosensor, controls VEGFR2 and Akt activities. Indeed, we show that PDE4D knockdown (KD) significantly blunts responses of HAECs to levels of FSS characteristically found in areas of the vasculature in which stenosis is prevalent. We propose that this effect may provide a new therapeutic avenue in modulating VEC behaviour at these sites by promoting an adaptive and vasculo-protective phenotype.
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Binoun-A-Egom C, Andreas A, Klimas J, Valentova V, Kruzliak P, Egom EE. B-type natriuretic peptide and heart failure: what can we learn from clinical trials? Clin Exp Pharmacol Physiol 2015; 42:881-887. [PMID: 25969125 DOI: 10.1111/1440-1681.12418] [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: 03/27/2015] [Revised: 04/24/2015] [Accepted: 05/07/2015] [Indexed: 11/26/2022]
Abstract
The B-type natriuretic peptide (BNP) may favour natriuresis and diuresis, making it an ideal drug to aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these has resulted in a better outcome. The current challenge for BNP research in acute HF lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP as well as a better integration of basic and clinical science.
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Affiliation(s)
| | - Angelo Andreas
- University of Toronto Scarborough Campus, Toronto, ON, Canada
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic
| | - Vanda Valentova
- Department of Medical Biology, Jessenius Medical Faculty in Martin, Comenius University, Martin, Slovak Republic
| | - Peter Kruzliak
- International Clinical Research Center, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic
| | - Emmanuel E Egom
- EGOM Clinical and Translational Research Services (ECTRS) Ltd, Halifax, NS, Canada
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Bazmara H, Soltani M, Sefidgar M, Bazargan M, Mousavi Naeenian M, Rahmim A. Blood flow and endothelial cell phenotype regulation during sprouting angiogenesis. Med Biol Eng Comput 2015; 54:547-58. [DOI: 10.1007/s11517-015-1341-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 07/01/2015] [Indexed: 11/24/2022]
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Bazmara H, Soltani M, Sefidgar M, Bazargan M, Mousavi Naeenian M, Rahmim A. The Vital Role of Blood Flow-Induced Proliferation and Migration in Capillary Network Formation in a Multiscale Model of Angiogenesis. PLoS One 2015; 10:e0128878. [PMID: 26047145 PMCID: PMC4457864 DOI: 10.1371/journal.pone.0128878] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 05/01/2015] [Indexed: 01/16/2023] Open
Abstract
Sprouting angiogenesis and capillary network formation are tissue scale phenomena. There are also sub-scale phenomena involved in angiogenesis including at the cellular and intracellular (molecular) scales. In this work, a multiscale model of angiogenesis spanning intracellular, cellular, and tissue scales is developed in detail. The key events that are considered at the tissue scale are formation of closed flow path (that is called loop in this article) and blood flow initiation in the loop. At the cellular scale, growth, migration, and anastomosis of endothelial cells (ECs) are important. At the intracellular scale, cell phenotype determination as well as alteration due to blood flow is included, having pivotal roles in the model. The main feature of the model is to obtain the physical behavior of a closed loop at the tissue scale, relying on the events at the cellular and intracellular scales, and not by imposing physical behavior upon it. Results show that, when blood flow is considered in the loop, the anastomosed sprouts stabilize and elongate. By contrast, when the loop is modeled without consideration of blood flow, the loop collapses. The results obtained in this work show that proper determination of EC phenotype is the key for its survival.
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Affiliation(s)
- Hossein Bazmara
- Department of Mechanical Engineering, K. N. T. University of Technology, Tehran, Iran
| | - Madjid Soltani
- Department of Mechanical Engineering, K. N. T. University of Technology, Tehran, Iran
- Division of Nuclear Medicine, Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America
- * E-mail:
| | - Mostafa Sefidgar
- Department of Mechanical Engineering, K. N. T. University of Technology, Tehran, Iran
| | - Majid Bazargan
- Department of Mechanical Engineering, K. N. T. University of Technology, Tehran, Iran
| | | | - Arman Rahmim
- Division of Nuclear Medicine, Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America
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Sangaralingham SJ, McKie PM, Ichiki T, Scott CG, Heublein DM, Chen HH, Bailey KR, Redfield MM, Rodeheffer RJ, Burnett JC. Circulating C-type natriuretic peptide and its relationship to cardiovascular disease in the general population. Hypertension 2015; 65:1187-94. [PMID: 25895587 DOI: 10.1161/hypertensionaha.115.05366] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/31/2015] [Indexed: 11/16/2022]
Abstract
C-type natriuretic peptide (CNP) is an endothelium-derived peptide that is released as a protective mechanism in response cardiovascular injury or disease. However, no studies have investigated circulating CNP, identifying clinical factors that may influence CNP and its relationship to cardiovascular disease in the general population. We studied 1841 randomly selected subjects from Olmsted County, MN (mean age, 63±11 years; 48% men). Plasma CNP was measured by a well-established radioimmunoassay and echocardiography, clinical characterization, and detailed medical record review were performed. We report that CNP circulates at various concentrations (median, 13 pg/mL), was unaffected by sex, was weakly associated by age, and that highest quartile of CNP identified a high-risk phenotype. Subjects with CNP in the highest quartile were associated with increased risk of myocardial infarction (multivariable-adjusted hazard ratio, 1.51; 95% confidence interval, 1.09-2.09; P=0.01) but not heart failure, cerebrovascular accidents, or death during a follow-up of 12 years. Addition of the highest quartile of CNP to clinical variables led to a modest increase in the integrated discrimination improvement for risk of myocardial infarction. In a large community-based cohort, elevated circulating CNP identified a high-risk phenotype that included cardiovascular comorbidities and left ventricular dysfunction, and provided evidence that highest concentrations of CNP potentially has prognostic value in predicting future risk of myocardial infarction. Together, these data from the general population highlight the potential value of CNP and support the need for additional studies to evaluate whether mechanisms regulating CNP could improve outcomes.
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Affiliation(s)
- S Jeson Sangaralingham
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN.
| | - Paul M McKie
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Tomoko Ichiki
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Christopher G Scott
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Denise M Heublein
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Horng H Chen
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Kent R Bailey
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Margaret M Redfield
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - Richard J Rodeheffer
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
| | - John C Burnett
- From the Cardiorenal Research Laboratory (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., J.C.B.), Divisions of Cardiovascular Diseases (S.J.S., P.M.M., T.I., D.M.H., H.H.C., M.M.R., R.J.R., J.C.B.), and Biomedical Statistics and Informatics (C.G.S., K.R.B.), Mayo Clinic, Rochester, MN
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Davis CA, Zambrano S, Anumolu P, Allen ACB, Sonoqui L, Moreno MR. Device-Based In Vitro Techniques for Mechanical Stimulation of Vascular Cells: A Review. J Biomech Eng 2015; 137:040801. [DOI: 10.1115/1.4029016] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 11/07/2014] [Indexed: 01/19/2023]
Abstract
The most common cause of death in the developed world is cardiovascular disease. For decades, this has provided a powerful motivation to study the effects of mechanical forces on vascular cells in a controlled setting, since these cells have been implicated in the development of disease. Early efforts in the 1970 s included the first use of a parallel-plate flow system to apply shear stress to endothelial cells (ECs) and the development of uniaxial substrate stretching techniques (Krueger et al., 1971, “An in Vitro Study of Flow Response by Cells,” J. Biomech., 4(1), pp. 31–36 and Meikle et al., 1979, “Rabbit Cranial Sutures in Vitro: A New Experimental Model for Studying the Response of Fibrous Joints to Mechanical Stress,” Calcif. Tissue Int., 28(2), pp. 13–144). Since then, a multitude of in vitro devices have been designed and developed for mechanical stimulation of vascular cells and tissues in an effort to better understand their response to in vivo physiologic mechanical conditions. This article reviews the functional attributes of mechanical bioreactors developed in the 21st century, including their major advantages and disadvantages. Each of these systems has been categorized in terms of their primary loading modality: fluid shear stress (FSS), substrate distention, combined distention and fluid shear, or other applied forces. The goal of this article is to provide researchers with a survey of useful methodologies that can be adapted to studies in this area, and to clarify future possibilities for improved research methods.
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Affiliation(s)
- Caleb A. Davis
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3120 e-mail:
| | - Steve Zambrano
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3120 e-mail:
| | - Pratima Anumolu
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3120 e-mail:
| | - Alicia C. B. Allen
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712-1801 e-mail:
| | - Leonardo Sonoqui
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3120 e-mail:
| | - Michael R. Moreno
- Department of Mechanical Engineering, Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843-3123 e-mail:
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Egom EE. BNP and Heart Failure: Preclinical and Clinical Trial Data. J Cardiovasc Transl Res 2015; 8:149-57. [PMID: 25771949 DOI: 10.1007/s12265-015-9619-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 03/05/2015] [Indexed: 12/11/2022]
Abstract
The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, has emerged as an important diagnostic, prognostic, and therapeutic tool in patients with heart failure (HF). The rapid incorporation into clinical practice of bioassays to BNP concentrations and pharmacological agents that augment the biological actions of this peptide such as nesiritide or vasopeptidase inhibitors has shown the potential for translational research to improve patient care. Despite the indirect evidence in support of a potential benefit from raising BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily confer cardiovascular benefits in patient with HF. Moreover, in experimental HF, the response to treatments targeting specific natriuretic peptide receptors (NPRs) signaling seems to be attenuated. A better understanding of the NPRs signaling in HF would be clinically relevant and thus required, in order to devise strategies to develop novel agents and technologies that directly target this signaling pathway.
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Affiliation(s)
- Emmanuel E Egom
- EGOM Clinical and Translational Research Services (ECTRS) Ltd, 5991 Spring garden Road, Halifax, Nova Scotia, Canada, B3H 4R7,
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Demirtas S, Karahan O, Yazici S, Guclu O, Caliskan A, Tezcan O, Yavuz C. Diagnostic value of plasma C-type natriuretic peptide levels in determination of the duration of mesenteric ischaemia. Cardiovasc J Afr 2014; 25:200-3. [PMID: 24967686 PMCID: PMC4241590 DOI: 10.5830/cvja-2014-033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/04/2014] [Indexed: 01/04/2023] Open
Abstract
Objective Mesenteric arteries release C-type natriuretic peptide (CNP), which hyperpolarises vascular smooth muscle. We measured the levels of this peptide after inducing mesenteric ischaemia over a series of time intervals, so as to determine its predictive value in demonstrating the severity of ischaemia in a rat model. Methods A total of 32 rats were allocated to four groups containing eight rats each. Basal CNP reference levels were measured in the control group, which was not exposed to any intervention. In groups I, II and III, mesenteric ischaemia was induced over three, six and nine hours, respectively, and plasma CNP levels were measured afterwards. Mesenteric ischaemia was induced by clamping the superior mesenteric artery. Results In comparison with the controls (2.38 ± 0.18 pg/ml), CNP levels were relatively lower in group I (2.54 ± 0.42 pg/ml). However, significant increases in plasma CNP levels were observed over longer periods of ischaemia in group II, at 5.23 ± 0.22 pg/ml, and in group III, at 6.19 ± 0.67 pg/ml (p < 0.05). A significant direct relationship was determined between plasma CNP levels and prolonged intervals of mesenteric ischaemia (R = 0.56, p < 0.001). Conclusion Measuring plasma CNP levels in patients with acute mesenteric ischaemia may be beneficial in estimating the time period over which the ischaemic injury has occurred.
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Affiliation(s)
- Sinan Demirtas
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey.
| | - Oguz Karahan
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
| | - Suleyman Yazici
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
| | - Orkut Guclu
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
| | - Ahmet Caliskan
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
| | - Orhan Tezcan
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
| | - Celal Yavuz
- Medical School of Dicle University, Department of Cardiovascular Surgery, Diyarbakir, Turkey
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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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Reid RA, Prickett TCR, Pullar BE, Darlow BA, Gullam JE, Espiner EA. C-type natriuretic peptide in complicated pregnancy: increased secretion precedes adverse events. J Clin Endocrinol Metab 2014; 99:1470-8. [PMID: 24446655 DOI: 10.1210/jc.2013-3758] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
CONTEXT C-type natriuretic peptide (CNP), a vasoactive product of the endothelium, is markedly increased during placentation in ovine pregnancy and is further stimulated by nutrient restriction. Whether CNP products change in human pregnancy is unknown. OBJECTIVES The objective of the study was to compare serial changes in maternal plasma CNP peptides during normal pregnancy with changes in pregnancy complicated by adverse events and relate these to fetal growth and placental CNP content. DESIGN This was a prospective observational study undertaken in a tertiary care center. METHODS We studied changes in maternal plasma aminoterminal proCNP (NTproCNP) and CNP at monthly intervals, fetal growth, and placental and umbilical plasma CNP peptides in 51 women, 28 of whom experienced an adverse event and 23 were uneventful. Age matched healthy nonpregnant women served as a reference range for NTproCNP. RESULTS Compared with nonpregnant women, maternal plasma NTproCNP in an uneventful pregnancy was significantly reduced from first sampling (16 wk gestation) until 36 weeks. In contrast, in complicated pregnancy, levels did not decline and were significantly higher (P < .001 by ANOVA) than in normal pregnancy from 20 weeks. Highest values occurred in women later developing hypertension and fetal growth disorders. Placental concentration of NTproCNP was unrelated to maternal NTproCNP but strongly correlated with cord plasma levels. CONCLUSIONS Maternal NTproCNP is significantly raised in women who later exhibit a range of obstetric adverse events. Lack of association with placental concentrations suggests that these changes represent an adaptive response within the maternal circulation to a threatened nutrient supply to the fetus.
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Affiliation(s)
- Rosemary A Reid
- Departments of Obstetrics and Gynaecology (R.A.R., B.E.P., J.E.G.), Medicine (T.C.R.P., E.A.E.), and Paediatrics (B.A.D.), University of Otago, Christchurch 8140, New Zealand
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