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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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2
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Lenzi A, De Cristofaro M, Biagini D, Ghimenti S, Armenia S, Pugliese NR, Masi S, Di Francesco F, Lomonaco T. Development of a high-throughput liquid chromatography-tandem mass spectrometry platform for the determination of intact natriuretic peptides in human plasma. Talanta 2024; 275:126077. [PMID: 38636440 DOI: 10.1016/j.talanta.2024.126077] [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: 12/16/2023] [Revised: 04/03/2024] [Accepted: 04/06/2024] [Indexed: 04/20/2024]
Abstract
We present an innovative, reliable, and antibody-free analytical method to determine multiple intact natriuretic peptides in human plasma. These biomolecules are routinely used to confirm the diagnosis and monitor the evolution of heart failure, so that their determination is essential to improve diagnosis and monitor the efficacy of treatment. However, common immunoassay kits suffer from main limitations due to high cross-reactivity with structurally similar species. In our method, we pre-treated the sample by combining salting-out with ammonium sulfate with microextraction by packed sorbent technique. Analyses were then carried out by ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. The use of 3-nitrobenzyl alcohol as a supercharger reagent enhanced the ESI ionization and improved the signal-to-noise ratio. The analytical protocol showed good linearity over one order of magnitude, recovery in the range of 94-105 %, and good intra- and inter-day reproducibility (RSD<20 %), and the presence of a matrix effect. Limits of detection were in the range of pg/mL for all peptides (0.2-20 pg/mL). Stability study in plasma samples demonstrated that proper protease inhibitors need to be included in blood collection tubes to avoid peptide degradation. Preliminary analyses on plasma samples from heart failure patients allow the quantification of ANP 1-28 as the most abundant species and the detection of ANP 5-28, BNP 1-32, and BNP 5-32. The method could be used to investigate how cross-reactivity issues among structurally similar species impact determinations by ELISA kits.
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Affiliation(s)
- Alessio Lenzi
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
| | - Mariano De Cristofaro
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
| | - Denise Biagini
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
| | - Silvia Ghimenti
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
| | - Silvia Armenia
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy.
| | - Nicola R Pugliese
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy.
| | - Stefano Masi
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy.
| | - Fabio Di Francesco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
| | - Tommaso Lomonaco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, Pisa, Italy.
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Giovou AE, Gladka MM, Christoffels VM. The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease. Cells 2024; 13:931. [PMID: 38891063 PMCID: PMC11172276 DOI: 10.3390/cells13110931] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
During mammalian heart development, the clustered genes encoding peptide hormones, Natriuretic Peptide A (NPPA; ANP) and B (NPPB; BNP), are transcriptionally co-regulated and co-expressed predominately in the atrial and ventricular trabecular cardiomyocytes. After birth, expression of NPPA and a natural antisense transcript NPPA-AS1 becomes restricted to the atrial cardiomyocytes. Both NPPA and NPPB are induced by cardiac stress and serve as markers for cardiovascular dysfunction or injury. NPPB gene products are extensively used as diagnostic and prognostic biomarkers for various cardiovascular disorders. Membrane-localized guanylyl cyclase receptors on many cell types throughout the body mediate the signaling of the natriuretic peptide ligands through the generation of intracellular cGMP, which interacts with and modulates the activity of cGMP-activated kinase and other enzymes and ion channels. The natriuretic peptide system plays a fundamental role in cardio-renal homeostasis, and its potent diuretic and vasodilatory effects provide compensatory mechanisms in cardiac pathophysiological conditions and heart failure. In addition, both peptides, but also CNP, have important intracardiac actions during heart development and homeostasis independent of the systemic functions. Exploration of the intracardiac functions may provide new leads for the therapeutic utility of natriuretic peptide-mediated signaling in heart diseases and rhythm disorders. Here, we review recent insights into the regulation of expression and intracardiac functions of NPPA and NPPB during heart development, homeostasis, and disease.
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Affiliation(s)
| | | | - Vincent M. Christoffels
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105AZ Amsterdam, The Netherlands; (A.E.G.); (M.M.G.)
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Hazim A, Nhola LF, Kailash V, Zhang S, Sandhu NP, Lerman A, Loprinzi CL, Ruddy KJ, Villarraga HR, Lewis B, Herrmann J. Changes in vascular function and correlation with cardiotoxicity in women with newly diagnosed breast cancer undergoing HER2-directed therapy with and without anthracycline/cyclophosphamide. EUROPEAN HEART JOURNAL OPEN 2024; 4:oead130. [PMID: 38239934 PMCID: PMC10794877 DOI: 10.1093/ehjopen/oead130] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/15/2023] [Accepted: 11/14/2023] [Indexed: 01/22/2024]
Abstract
Aims The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results Single-centre, prospective cohort study of women with newly diagnosed stage 1-3 HER2-positive breast cancer undergoing HER2-Tx +/- AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1β)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of >10% to a value <53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1β levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1β: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients.
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Affiliation(s)
| | - Lara F Nhola
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Vidur Kailash
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Song Zhang
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Nicole P Sandhu
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Bradley Lewis
- Department of Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Joerg Herrmann
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
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Li J, Zhuo N, Zhang J, Sun Q, Si J, Wang K, Zhi D. The loading of C-type natriuretic peptides improved hemocompatibility and vascular regeneration of electrospun poly(ε-caprolactone) grafts. Acta Biomater 2022; 151:304-316. [PMID: 36002127 DOI: 10.1016/j.actbio.2022.08.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/02/2022] [Accepted: 08/15/2022] [Indexed: 11/01/2022]
Abstract
As a result of thrombosis or intimal hyperplasia, synthetic artificial vascular grafts had a low success rate when they were used to replace small-diameter arteries (inner diameter < 6 mm). C-type natriuretic peptides (CNP) have anti-thrombotic effects, and can promote endothelial cell (EC) proliferation and inhibit vascular smooth muscle cell (SMC) over-growth. In this study, poly(ε-caprolactone) (PCL) vascular grafts loaded with CNP (PCL-CNP) were constructed by electrospinning. The PCL-CNP grafts were able to continuously release CNP at least 25 days in vitro. The results of scanning electron microscopy (SEM) and mechanical testing showed that the loading of CNP did not change the microstructure and mechanical properties of the PCL grafts. In vitro blood compatibility analysis displayed that PCL-CNP grafts could inhibit thrombin activity and reduce platelet adhesion and activation. In vitro cell experiments demonstrated that PCL-CNP grafts activated ERK1/2 and Akt signaling in human umbilical vein endothelial cells (HUVECs), as well as increased cyclin D1 expression, enhanced proliferation and migration, and increased vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production. The rabbit arteriovenous (AV)-shunt ex vitro indicated that CNP loading significantly improved the antithrombogenicity of PCL grafts. The assessment of vascular grafts in rat abdominal aorta implantation model displayed that PCL-CNP grafts promoted the regeneration of ECs and contractile SMCs, modulated macrophage polarization toward M2 phenotype, and enhanced extracellular matrix remodeling. These findings confirmed for the first time that loading CNP is an effective approach to improve the hemocompatibility and vascular regeneration of synthetic vascular grafts. STATEMENT OF SIGNIFICANCE: Small-diameter (< 6 mm) vascular grafts (SDVGs) have not been made clinically available due to their prevalence of thrombosis, limited endothelial regeneration and intimal hyperplasia. The incorporation of bioactive molecules into SDVGs serves as an effective solution to improve hemocompatibility and endothelialization. In this study, for the first time, we loaded C-type natriuretic peptides (CNP) into PCL grafts by electrospunning and confirmed the effectiveness of loading CNP on improving the hemocompatibility and vascular regeneration of artificial vascular grafts. Regenerative advantages included enhancement of endothelialization, modulation of macrophage polarization toward M2 phenotypes, and improved contractile smooth muscle cell regeneration. Our investigation brings attention to CNP as a valuable bioactive molecule for modifying cardiovascular biomaterial.
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Affiliation(s)
- Jing Li
- Department of Ultrasound, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
| | - Na Zhuo
- Department of Ultrasound, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Jingai Zhang
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Qiqi Sun
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jianghua Si
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Kai Wang
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Dengke Zhi
- College of Life Sciences, Nankai University, Tianjin 300071, China.
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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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Manfra O, Calamera G, Froese A, Arunthavarajah D, Surdo NC, Meier S, Melleby AO, Aasrum M, Aronsen JM, Nikolaev VO, Zaccolo M, Moltzau LR, Levy FO, Andressen KW. CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors. Cardiovasc Res 2022; 118:1506-1519. [PMID: 33970224 PMCID: PMC9074987 DOI: 10.1093/cvr/cvab167] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 05/07/2021] [Indexed: 11/14/2022] Open
Abstract
AIMS Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signalling in adult cardiomyocytes. METHODS AND RESULTS We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crest increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. CONCLUSION These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP, is able to induce lusitropic and negative inotropic responses.
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Affiliation(s)
- Ornella Manfra
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Gaia Calamera
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Alexander Froese
- German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Hamburg, Germany
| | - Dulasi Arunthavarajah
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Nicoletta C Surdo
- Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK
| | - Silja Meier
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Arne Olav Melleby
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Monica Aasrum
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Jan Magnus Aronsen
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Viacheslav O Nikolaev
- German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Hamburg, Germany
| | - Manuela Zaccolo
- Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK
| | - Lise Román Moltzau
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Finn Olav Levy
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
| | - Kjetil Wessel Andressen
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway
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8
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Gidlöf O. Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure. Front Physiol 2021; 12:650124. [PMID: 34721050 PMCID: PMC8548580 DOI: 10.3389/fphys.2021.650124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022] Open
Abstract
The natriuretic peptide system (NPS) plays a fundamental role in maintaining cardiorenal homeostasis, and its potent filling pressure-regulated diuretic and vasodilatory effects constitute a beneficial compensatory mechanism in heart failure (HF). Leveraging the NPS for therapeutic benefit in HF has been the subject of intense investigation during the last three decades and has ultimately reached widespread clinical use in the form of angiotensin receptor-neprilysin inhibition (ARNi). NPS enhancement via ARNi confers beneficial effects on mortality and hospitalization in HF, but inhibition of neprilysin leads to the accumulation of a number of other vasoactive peptides in the circulation, often resulting in hypotension and raising potential concerns over long-term adverse effects. Moreover, ARNi is less effective in the large group of HF patients with preserved ejection fraction. Alternative approaches for therapeutic augmentation of the NPS with increased specificity and efficacy are therefore warranted, and are now becoming feasible particularly with recent development of RNA therapeutics. In this review, the current state-of-the-art in terms of experimental and clinical strategies for NPS augmentation and their implementation will be reviewed and discussed.
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Affiliation(s)
- Olof Gidlöf
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
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9
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Cabiati M, Sgalippa A, Federico G, Del Ry S. C-type natriuretic peptide in childhood obesity. Peptides 2021; 145:170639. [PMID: 34425175 DOI: 10.1016/j.peptides.2021.170639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/23/2021] [Accepted: 08/17/2021] [Indexed: 11/30/2022]
Abstract
According to the World Health Organization obesity is the result of an energy imbalance between calories assumed and expended and over the past 30 years its incidence has dramatically increased. Recently, the problem of obesity has drastically increased also in childhood, assuming a social relevance. Childhood obesity, in fact, increases the possibility to be obese in adulthood, representing a risk for cardiovascular morbidity and mortality. Aim of this review was to carry out a revision of the literature on childhood obesity focusing on natriuretic peptides (NPs) and in particular on the role of C-type natriuretic peptide (CNP). In obesity NPs play a fundamental role in the regulation of body weight and energy metabolism. Data on plasma CNP levels in children are scarce. The review of the literature relating to the role of CNP in adolescents showed a progressive reduction in the CNP plasma levels in overweight/obese adolescents compared to normal-weight subjects, as previously observed in obese adults, as well as a different modulation in CNP mRNA expression. An independent association between CNP levels and obesity as well as a significant association with the endothelial dysfunction index was reported, indicating that the peptide could play a very important role as a marker of risk of developing obesity. The results of these studies indicate the importance of adopting healthy lifestyles to improve glucometabolic control as well as to provide the rationale for designing and developing new drugs to modulate the NPs system.
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Affiliation(s)
- Manuela Cabiati
- Laboratory of Biochemistry and Molecular Biology, Institute of Clinical Physiology, CNR, Pisa, Italy
| | - Agnese Sgalippa
- Laboratory of Biochemistry and Molecular Biology, Institute of Clinical Physiology, CNR, Pisa, Italy
| | - Giovanni Federico
- Unit of Pediatric Endocrinology and Diabetes, Dep. Clinical and Experimental Medicine, University of Pisa, Italy
| | - Silvia Del Ry
- Laboratory of Biochemistry and Molecular Biology, Institute of Clinical Physiology, CNR, Pisa, Italy.
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10
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Kuwahara K. The natriuretic peptide system in heart failure: Diagnostic and therapeutic implications. Pharmacol Ther 2021; 227:107863. [PMID: 33894277 DOI: 10.1016/j.pharmthera.2021.107863] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
Natriuretic peptides, which are activated in heart failure, play an important cardioprotective role. The most notable of the cardioprotective natriuretic peptides are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are abundantly expressed and secreted in the atrium and ventricles, respectively, and C-type natriuretic peptide (CNP), which is expressed mainly in the vasculature, central nervous system, and bone. ANP and BNP exhibit antagonistic effects against angiotensin II via diuretic/natriuretic actions, vasodilatory actions, and inhibition of aldosterone secretion, whereas CNP is involved in the regulation of vascular tone and blood pressure, among other roles. ANP and BNP are of particular interest with respect to heart failure, as their levels, most notably BNP and N-terminal proBNP-a cleavage product produced when proBNP is processed to mature BNP-are increased in patients with heart failure. Furthermore, the identification of natriuretic peptides as sensitive markers of cardiac load has driven significant research into their physiological roles in cardiovascular homeostasis and disease, as well as their potential use as both biomarkers and therapeutics. In this review, I discuss the physiological functions of the natriuretic peptide family, with a particular focus on the basic research that has led to our current understanding of its roles in maintaining cardiovascular homeostasis, and the pathophysiological implications for the onset and progression of heart failure. The clinical significance and potential of natriuretic peptides as diagnostic and/or therapeutic agents are also discussed.
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Affiliation(s)
- Koichiro Kuwahara
- Department of Cardiovascular Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
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11
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He H, Cao M, Hu J, Zhu L, Su C, Du S, Yang J, Tang Y, Chen L. Fluorescent turn-on assay of C-type natriuretic peptide using a molecularly imprinted ratiometric fluorescent probe with high selectivity and sensitivity. Mikrochim Acta 2020; 187:614. [PMID: 33073313 DOI: 10.1007/s00604-020-04583-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 09/29/2020] [Indexed: 01/06/2023]
Abstract
A novel molecularly imprinted ratiometric fluorescent probe was fabricated by simple sol-gel polymerization for selective and sensitive assay of C-type natriuretic peptide (CNP) in biosamples. Both the nitrobenzoxadiazole (NBD) and carbon dots (CDs) were located on the surface of silica, used as the detection signal and reference signal, respectively. For the turn-on-based probe, the fluorescence intensity of NBD could be quantitatively enhanced by CNP based on the strategy of photo-induced electron transfer (PET), while the fluorescence of CDs remained unchanged. The obtained probe exhibited excellent recognition selectivity and fast kinetics to CNP templates, and also showed good stability. The linear range of CNP determination was 5-80 pg mL-1 with a low detection limit of 2.87 pg mL-1. Finally, the probe was successfully applied to determine CNP in human serum samples and attained high recoveries between 97.3 and 104% with precisions below 4.7%. The result indicates that the proposed method has promising potential for the assay of trace peptides in complex matrices. Schematic illustration for the formation and determination mechanism of the probe.
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Affiliation(s)
- Hongliang He
- Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Min Cao
- Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Jingwan Hu
- Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Ling Zhu
- Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Chang Su
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China
| | - Shuhu Du
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Jian Yang
- Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
| | - Yulin Tang
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China.
| | - Lina Chen
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
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12
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Lerner Y, Hanout W, Ben-Uliel SF, Gani S, Leshem MP, Qvit N. Natriuretic Peptides as the Basis of Peptide Drug Discovery for Cardiovascular Diseases. Curr Top Med Chem 2020; 20:2904-2921. [PMID: 33050863 DOI: 10.2174/1568026620666201013154326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/14/2020] [Accepted: 09/25/2020] [Indexed: 01/14/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading global cause of death, accounting for more than 17.6 million deaths per year in 2016, a number that is expected to grow to more than 23.6 million by 2030. While many technologies are currently under investigation to improve the therapeutic outcome of CVD complications, only a few medications have been approved. Therefore, new approaches to treat CVD are urgently required. Peptides regulate numerous physiological processes, mainly by binding to specific receptors and inducing a series of signals, neurotransmissions or the release of growth factors. Importantly, peptides have also been shown to play an important role in the circulatory system both in physiological and pathological conditions. Peptides, such as angiotensin II, endothelin, urotensin-II, urocortins, adrenomedullin and natriuretic peptides have been implicated in the control of vascular tone and blood pressure as well as in CVDs such as congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Hence it is not surprising that peptides are becoming important therapeutic leads in CVDs. This article will review the current knowledge on peptides and their role in the circulatory system, focusing on the physiological roles of natriuretic peptides in the cardiovascular system and their implications in CVDs.
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Affiliation(s)
- Yana Lerner
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Wessal Hanout
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Shulamit Fluss Ben-Uliel
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Samar Gani
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Michal Pellach Leshem
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, P.O. Box 1589, Safed, Israel
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13
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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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14
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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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15
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Moyes AJ, Chu SM, Aubdool AA, Dukinfield MS, Margulies KB, Bedi KC, Hodivala-Dilke K, Baliga RS, Hobbs AJ. C-type natriuretic peptide co-ordinates cardiac structure and function. Eur Heart J 2020; 41:1006-1020. [PMID: 30903134 PMCID: PMC7068173 DOI: 10.1093/eurheartj/ehz093] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/21/2018] [Accepted: 02/26/2019] [Indexed: 12/11/2022] Open
Abstract
AIMS C-type natriuretic peptide (CNP) is an essential endothelium-derived signalling species that governs vascular homoeostasis; CNP is also expressed in the heart but an intrinsic role for the peptide in cardiac function is not established. Herein, we employ unique transgenic strains with cell-specific deletion of CNP to define a central (patho)physiological capacity of CNP in maintaining heart morphology and contractility. METHODS AND RESULTS Cardiac structure and function were explored in wild type (WT), cardiomyocyte (cmCNP-/-), endothelium (ecCNP-/-), and fibroblast (fbCNP-/-)-specific CNP knockout mice, and global natriuretic peptide receptor (NPR)-B-/-, and NPR-C-/- animals at baseline and in experimental models of myocardial infarction and heart failure (HF). Endothelium-specific deletion of CNP resulted in impaired coronary responsiveness to endothelium-dependent- and flow-mediated-dilatation; changes mirrored in NPR-C-/- mice. Ex vivo, global ischaemia resulted in larger infarcts and diminished functional recovery in cmCNP-/- and NPR-C-/-, but not ecCNP-/-, vs. WT. The cardiac phenotype of cmCNP-/-, fbCNP-/-, and NPR-C-/- (but not ecCNP-/- or NPR-B-/-) mice was more severe in pressure overload- and sympathetic hyperactivation-induced HF compared with WT; these adverse effects were rescued by pharmacological CNP administration in WT, but not NPR-C-/-, mice. At a molecular level, CNP/NPR-C signalling is impaired in human HF but attenuates activation of well-validated pro-hypertrophic and pro-fibrotic pathways. CONCLUSION C-type natriuretic peptide of cardiomyocyte, endothelial and fibroblast origins co-ordinates and preserves cardiac structure, function, and coronary vasoreactivity via activation of NPR-C. Targeting NPR-C may prove an innovative approach to treating HF and ischaemic cardiovascular disorders.
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Affiliation(s)
- Amie J Moyes
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Sandy M Chu
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Aisah A Aubdool
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Matthew S Dukinfield
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Kenneth B Margulies
- Heart Failure and Transplant Program, Perelman School of Medicine, University of Pennsylvania, Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Kenneth C Bedi
- Heart Failure and Transplant Program, Perelman School of Medicine, University of Pennsylvania, Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Reshma S Baliga
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
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16
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Hussain A, Bennett RT, Tahir Z, Isaac E, Chaudhry MA, Qadri SS, Loubani M, Morice AH. Differential effects of atrial and brain natriuretic peptides on human pulmonary artery: An in vitro study. World J Cardiol 2019; 11:236-243. [PMID: 31754411 PMCID: PMC6859300 DOI: 10.4330/wjc.v11.i10.236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 08/31/2019] [Accepted: 09/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prevalence of cardiovascular diseases, especially heart failure, continues to rise worldwide. In heart failure, increasing levels of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are associated with a worsening of heart failure and a poor prognosis.
AIM To test whether a high concentration of BNP would inhibit relaxation to ANP.
METHODS Pulmonary arteries were dissected from disease-free areas of lung resection, as well as pulmonary artery rings of internal diameter 2.5–3.5 mm and 2 mm long, were prepared. Pulmonary artery rings were mounted in a multiwire myograph, and a basal tension of 1.61gf was applied. After equilibration for 60 min, rings were pre-constricted with 11.21 µmol/L PGF2α (EC80), and concentration response curves were constructed to vasodilators by cumulative addition to the myograph chambers.
RESULTS Although both ANP and BNP were found to vasodilate the pulmonary vessels, ANP is more potent than BNP. pEC50 of ANP and BNP were 8.96 ± 0.21 and 7.54 ± 0.18, respectively, and the maximum efficacy (Emax) for ANP and BNP was -2.03 gf and -0.24 gf, respectively. After addition of BNP, the Emax of ANP reduced from -0.96gf to -0.675gf (P = 0.28).
CONCLUSION BNP could be acting as a partial agonist in small human pulmonary arteries, and inhibits relaxation to ANP. Elevated levels of circulating BNP could be responsible for the worsening of decompensated heart failure. This finding could also explain the disappointing results seen in clinical trials of ANP and BNP analogues for the treatment of heart failure.
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Affiliation(s)
- Azar Hussain
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Robert T Bennett
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Zaheer Tahir
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Emmanuel Isaac
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Mubarak A Chaudhry
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Syed S Qadri
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Mahmoud Loubani
- Department of Cardiothoracic Surgery, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
| | - Alyn H Morice
- Centre for Cardiovascular and Metabolic Research, Hull York Medical School, Castle Hill Hospital, Cottingham HU16 5JQ, United Kingdom
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17
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Rubattu S, Volpe M. Natriuretic Peptides in the Cardiovascular System: Multifaceted Roles in Physiology, Pathology and Therapeutics. Int J Mol Sci 2019; 20:ijms20163991. [PMID: 31426320 PMCID: PMC6721730 DOI: 10.3390/ijms20163991] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/15/2019] [Indexed: 12/13/2022] Open
Abstract
The natriuretic peptides (NPs) family includes a class of hormones and their receptors needed for the physiological control of cardiovascular functions. The discovery of NPs provided a fundamental contribution into our understanding of the physiological regulation of blood pressure, and of heart and kidney functions. NPs have also been implicated in the pathogenesis of several cardiovascular diseases (CVDs), including hypertension, atherosclerosis, heart failure, and stroke. A fine comprehension of the molecular mechanisms dependent from NPs and underlying the promotion of cardiovascular damage has contributed to improve our understanding of the molecular basis of all major CVDs. Finally, the opportunity to target NPs in order to develop new therapeutic tools for a better treatment of CVDs has been developed over the years. The current Special Issue of the Journal covers all major aspects of the molecular implications of NPs in physiology and pathology of the cardiovascular system, including NP-based therapeutic approaches.
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Affiliation(s)
- Speranza Rubattu
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
- IRCCS Neuromed, 86077 Pozzilli (Isernia), Italy.
| | - Massimo Volpe
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
- IRCCS Neuromed, 86077 Pozzilli (Isernia), Italy.
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18
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Hardy-Rando E, Fernandez-Patron C. Emerging pathways of communication between the heart and non-cardiac organs. J Biomed Res 2019; 33:145-155. [PMID: 29970623 PMCID: PMC6551427 DOI: 10.7555/jbr.32.20170137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis – a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.
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Affiliation(s)
- Eugenio Hardy-Rando
- Biotechnology Laboratory, Study Center for Research and Biological Evaluations, Institute of Pharmacy and Foods, University of Havana, Havana PO Box 430, Cuba
| | - Carlos Fernandez-Patron
- Department of Biochemistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
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19
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Moyes AJ, Hobbs AJ. C-type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature. Int J Mol Sci 2019; 20:E2281. [PMID: 31072047 PMCID: PMC6539462 DOI: 10.3390/ijms20092281] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 04/30/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022] Open
Abstract
C-type natriuretic peptide (CNP) is an autocrine and paracrine mediator released by endothelial cells, cardiomyocytes and fibroblasts that regulates vital physiological functions in the cardiovascular system. These roles are conveyed via two cognate receptors, natriuretic peptide receptor B (NPR-B) and natriuretic peptide receptor C (NPR-C), which activate different signalling pathways that mediate complementary yet distinct cellular responses. Traditionally, CNP has been deemed the endothelial component of the natriuretic peptide system, while its sibling peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are considered the endocrine guardians of cardiac function and blood volume. However, accumulating evidence indicates that CNP not only modulates vascular tone and blood pressure, but also governs a wide range of cardiovascular effects including the control of inflammation, angiogenesis, smooth muscle and endothelial cell proliferation, atherosclerosis, cardiomyocyte contractility, hypertrophy, fibrosis, and cardiac electrophysiology. This review will focus on the novel physiological functions ascribed to CNP, the receptors/signalling mechanisms involved in mediating its cardioprotective effects, and the development of therapeutics targeting CNP signalling pathways in different disease pathologies.
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Affiliation(s)
- Amie J Moyes
- William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
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20
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Matsuo A, Nagai-Okatani C, Nishigori M, Kangawa K, Minamino N. Natriuretic peptides in human heart: Novel insight into their molecular forms, functions, and diagnostic use. Peptides 2019; 111:3-17. [PMID: 30120963 DOI: 10.1016/j.peptides.2018.08.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 08/12/2018] [Accepted: 08/13/2018] [Indexed: 01/16/2023]
Abstract
Among the three natriuretic peptides, atrial/A-type natriuretic peptide (ANP) and brain/B-type natriuretic peptide (BNP) are primarily produced by, and secreted from, heart tissue. They maintain cardiovascular homeostasis by binding to natriuretic peptide receptor-A. Since plasma ANP and BNP concentrations, as well as expression, are elevated in response to increased body fluid volume and pressure load on the heart wall, these peptides are widely utilized as diagnostic biomarkers for evaluating heart failure. Regardless of their high utility, differences in their molecular forms between healthy and diseased subjects and how these relate to pathophysiology have not well been examined. Recent studies have shown that the circulating molecular forms of ANP and BNP are not uniform; bioactive α-ANP is the major ANP form, whereas the weakly active proBNP is the major BNP form. The relative ratios of the different molecular forms are altered under different pathophysiological conditions. These facts indicate that detailed measurements of each form may provide useful information on the pathophysiological state of heart tissue. Here, we revisit the relationship between the molecular forms of, and pathophysiological alterations in, human ANP and BNP and discuss the possible utility of the measurement of each of the molecular forms. The third peptide, C-type natriuretic peptide, activates natriuretic peptide receptor-B, but little is known about its production and function in the heart because of its extremely low levels. However, through recent studies, its role in the heart is gradually becoming clear. Here, we summarize its molecular forms, assay systems, and functions in the heart.
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Affiliation(s)
- Ayaka Matsuo
- Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan
| | - Chiaki Nagai-Okatani
- Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
| | - Mitsuhiro Nishigori
- Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan
| | - Kenji Kangawa
- Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan
| | - Naoto Minamino
- Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan.
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21
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Krichevskiy LA, Kozlov IA. Natriuretic Peptides in Cardiac Anesthesia and Intensive Care. J Cardiothorac Vasc Anesth 2018; 33:1407-1419. [PMID: 30228053 DOI: 10.1053/j.jvca.2018.08.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Indexed: 01/16/2023]
Abstract
Natriuretic peptides, predominantly B-type, are widely used in cardiology as prognostic and diagnostic biomarkers or, much less often, as a substantive treatment tool. They are hormones that are produced mainly in the myocardium in response to overload and ischemia, and their level quite accurately reflects the degree of myocardial dysfunction. Although their use in cardiac anesthesia and intensive care setting seems to be very beneficial for assessing the risk of acute disturbance of myocardial function or its laboratory monitoring, the actual significance of natriuretic peptides in this area is not yet recognized. This is due to the lack of clear diagnostic and prognostic values for these biomarkers supported by high-quality researches. On the basis of the available data, main advantages, existing difficulties, and most effective ways of using natriuretic peptides for determining the risk of heart surgery and assessing the severity of sepsis, pneumonia, and other critical conditions have been discussed in this review. In addition, the expediency of using natriuretic peptides as target parameters for goal-oriented therapy and as a substantive tool for treatment is considered.
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Affiliation(s)
- Lev A Krichevskiy
- Department of Anesthesiology and Intensive Care, City Clinical Hospital n.a. S.S.Yudin, Department of Health of Moscow, Moscow, Russia.
| | - Igor A Kozlov
- Department of Anaesthesiology, Moscow Regional Research Clinical Institute n.a. M.F. Vladimirskiy, Moscow, Russia
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22
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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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Fu S, Ping P, Wang F, Luo L. Synthesis, secretion, function, metabolism and application of natriuretic peptides in heart failure. J Biol Eng 2018; 12:2. [PMID: 29344085 PMCID: PMC5766980 DOI: 10.1186/s13036-017-0093-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 12/21/2017] [Indexed: 12/11/2022] Open
Abstract
As a family of hormones with pleiotropic effects, natriuretic peptide (NP) system includes atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), dendroaspis NP and urodilatin, with NP receptor-A (guanylate cyclase-A), NP receptor-B (guanylate cyclase-B) and NP receptor-C (clearance receptor). These peptides are genetically distinct, but structurally and functionally related for regulating circulatory homeostasis in vertebrates. In humans, ANP and BNP are encoded by NP precursor A (NPPA) and NPPB genes on chromosome 1, whereas CNP is encoded by NPPC on chromosome 2. NPs are synthesized and secreted through certain mechanisms by cardiomyocytes, fibroblasts, endotheliocytes, immune cells (neutrophils, T-cells and macrophages) and immature cells (embryonic stem cells, muscle satellite cells and cardiac precursor cells). They are mainly produced by cardiovascular, brain and renal tissues in response to wall stretch and other causes. NPs provide natriuresis, diuresis, vasodilation, antiproliferation, antihypertrophy, antifibrosis and other cardiometabolic protection. NPs represent body's own antihypertensive system, and provide compensatory protection to counterbalance vasoconstrictor-mitogenic-sodium retaining hormones, released by renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS). NPs play central roles in regulation of heart failure (HF), and are inactivated through not only NP receptor-C, but also neutral endopeptidase (NEP), dipeptidyl peptidase-4 and insulin degrading enzyme. Both BNP and N-terminal proBNP are useful biomarkers to not only make the diagnosis and assess the severity of HF, but also guide the therapy and predict the prognosis in patients with HF. Current NP-augmenting strategies include the synthesis of NPs or agonists to increase NP bioactivity and inhibition of NEP to reduce NP breakdown. Nesiritide has been established as an available therapy, and angiotensin receptor blocker NEP inhibitor (ARNI, LCZ696) has obtained extremely encouraging results with decreased morbidity and mortality. Novel pharmacological approaches based on NPs may promote a therapeutic shift from suppressing the RAAS and SNS to re-balancing neuroendocrine dysregulation in patients with HF. The current review discussed the synthesis, secretion, function and metabolism of NPs, and their diagnostic, therapeutic and prognostic values in HF.
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Affiliation(s)
- Shihui Fu
- Department of Geriatric Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, 100853 China
- Department of Cardiology and Hainan Branch, Chinese People’s Liberation Army, General Hospital, Beijing, China
| | - Ping Ping
- Department of Pharmaceutical Care, Chinese People’s, Liberation Army General Hospital, Beijing, China
| | - Fengqi Wang
- Department of Cardiology and Hainan Branch, Chinese People’s Liberation Army, General Hospital, Beijing, China
| | - Leiming Luo
- Department of Geriatric Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, 100853 China
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Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-3-319-54579-0_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
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Meier S, Andressen KW, Aronsen JM, Sjaastad I, Hougen K, Skomedal T, Osnes JB, Qvigstad E, Levy FO, Moltzau LR. PDE3 inhibition by C-type natriuretic peptide-induced cGMP enhances cAMP-mediated signaling in both non-failing and failing hearts. Eur J Pharmacol 2017; 812:174-183. [PMID: 28697992 DOI: 10.1016/j.ejphar.2017.07.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 07/04/2017] [Accepted: 07/05/2017] [Indexed: 12/28/2022]
Abstract
We have previously shown that the natriuretic peptide receptor B (NPR-B) agonist C-type natriuretic peptide (CNP) enhances cyclic adenosine 3´,5´-monophosphate (cAMP)-mediated signaling in failing hearts, through cyclic guanosine 3´,5´-monophosphate (cGMP)-mediated phosphodiesterase (PDE) 3 inhibition. As several signaling pathways are importantly changed in failing hearts, it could not be taken for granted that this crosstalk would be the same in non-failing hearts. Thus, we wanted to clarify to which extent this effect of CNP occurred also in non-failing hearts. Inotropic and lusitropic responses were measured in muscle strips and cGMP levels, localized cAMP levels, cAMP-PDE activity and mRNA levels were analyzed in isolated cardiomyocytes from left ventricles of non-failing and failing rat hearts. CNP increased cGMP and enhanced β1- and β2-adrenoceptor-mediated inotropic and β1-adrenoceptor-mediated lusitropic responses, in non-failing and failing hearts. The NPR-A agonist brain natriuretic peptide (BNP) increased cGMP, but did not affect inotropic or lusitropic responses, indicating different compartmentation of cGMP from the two natriuretic peptide receptors. cAMP-PDE activity of PDE3 was concentration-dependently inhibited by cGMP with the same potency and to the same extent in non-failing and failing cardiomyocytes. CNP enhanced β1-adrenoceptor-induced cAMP increase in living cardiomyocytes in the absence, but not in the presence of a PDE3 inhibitor indicating involvement of PDE3. In summary, CNP sensitizes cAMP-mediated signaling in non-failing as in failing hearts, via NPR-B-mediated increase of cGMP that inhibits the cAMP-PDE activity of PDE3.
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Affiliation(s)
- Silja Meier
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Kjetil Wessel Andressen
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Jan Magnus Aronsen
- Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Institute for Experimental Medical Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Bjørknes College, Oslo, Norway
| | - Ivar Sjaastad
- Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Institute for Experimental Medical Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Karina Hougen
- Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Institute for Experimental Medical Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Tor Skomedal
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Jan-Bjørn Osnes
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Eirik Qvigstad
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Finn Olav Levy
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
| | - Lise Román Moltzau
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
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Li T, Cheng HJ, Ohte N, Hasegawa H, Morimoto A, Herrington DM, Little WC, Li W, Cheng CP. C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure. J Pharmacol Exp Ther 2016; 357:545-53. [PMID: 27026682 PMCID: PMC4885509 DOI: 10.1124/jpet.115.231696] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/28/2016] [Indexed: 01/20/2023] Open
Abstract
In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 μg/kg plus 0.4 μg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.
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Affiliation(s)
- Tiankai Li
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Heng-Jie Cheng
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Nobuyuki Ohte
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Hiroshi Hasegawa
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Atsushi Morimoto
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - David M Herrington
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - William C Little
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Weimin Li
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
| | - Che Ping Cheng
- Wake Forest School of Medicine, Winston-Salem, North Carolina (H.J.C., N.O., H.H., A.M., D.M.H., W.C.L., C.P.C.), and the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L., H.J.C, W.L., C.P.C)
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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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Abstract
Risk prediction in patients admitted with acute decompensated heart failure (ADHF) remains a challenge. Biomarkers may improve risk prediction, which in turn may help to better inform patients regarding short-term and long-term prognosis, therapy and care. Most data on biomarkers have been derived from patient cohorts with chronic heart failure. In ADHF, currently, risk tools largely rely on common clinical and biochemical parameters. However, ADHF is not a single disease. It presents in various manners and different etiologies may underlie ADHF, which are reflected by different biomarkers. In the last decade, many studies have reported the prognostic value of these biomarkers. These studies have attempted to describe a value for statistical modeling, e.g., reclassification indices, in an effort to report incremental value over a clinical model or the "gold standard". However, the overall incremental predictive value of biomarkers has been modest compared to already existing clinical models. Natriuretic peptides, e.g., (NTpro-)BNP, are the benchmark, but head-to-head comparisons show that there are novel biomarkers with comparable prognostic value. Multimarker strategies may provide superior risk stratification. Future studies should elucidate cost-effectiveness of single or combined biomarker testing. The purpose of this review was to provide an update on current biomarkers and to identify new promising biomarkers than can be used in prognostication of acute heart failure.
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Lin J, Han Z, Li H, Chen SY, Li X, Liu P, Wang Y, Tang C, Du J, Jin H. Plasma C-type natriuretic peptide as a predictor for therapeutic response to metoprolol in children with postural tachycardia syndrome. PLoS One 2015; 10:e0121913. [PMID: 25811760 PMCID: PMC4374798 DOI: 10.1371/journal.pone.0121913] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 02/05/2015] [Indexed: 01/17/2023] Open
Abstract
POTS is a global public-health disease, but predictor for therapeutic response to metoprolol in children with POTS is lacking. This study was designed to investigate predictive value of plasma C-type natriuretic peptide (CNP) in the therapeutic efficacy of metoprolol on postural tachycardia syndrome (POTS) in children. Totally 34 children with POTS and 27 healthy children were included in the study. The head-up test or head-up tilt test was used to check heart rate and blood pressure from supine to upright in subjects. A double antibody (competitive) sandwich immunoluminometric assay was used to detect plasma CNP. Metoprolol was used to treat children with POTS. The difference in plasma concentrations of CNP between responders and non-responders was compared. An ROC curve was used to analyze plasma CNP to predict efficacy of metoprolol on POTS in children. Plasma CNP in children with POTS was significantly higher than that of healthy children [(51.9 ± 31.4) vs. (25.1 ± 19.1) pg/ml, P <0.001]. Plasma CNP in responders to metoprolol was significantly higher than non-responders [(59.1 ± 33.5) vs. (34.8 ± 16.7) pg/ml, P = 0.037] before treatment. The ROC curve showed that area under the curve was 0.821 (95% CI 0.642–0.999). The cut-off value of plasma CNP > 32.55 pg/ml yielded a sensitivity of 95.8% and specificity of 70% in predicting therapeutic efficacy of metoprolol on POTS children. Plasma CNP might serve as a useful predictor for the therapeutic efficacy of metoprolol on POTS in children.
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Affiliation(s)
- Jing Lin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Zhenhui Han
- Department of Pediatrics, Kaifeng Children’s Hospital, Henan, China
| | - Hongxia Li
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Selena Ying Chen
- University of California San Diego, La Jolla, California, United States of America
| | - Xueying Li
- Department of Medical Statistics, Peking University First Hospital, Beijing, China
| | - Ping Liu
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yuli Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Chaoshu Tang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
- * 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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Li P, Tang XD, Cai ZX, Qiu JJ, Lin XL, Zhu T, Owusu L, Guo HS. CNP signal pathway up-regulated in rectum of depressed rats and the interventional effect of Xiaoyaosan. World J Gastroenterol 2015; 21:1518-1530. [PMID: 25663771 PMCID: PMC4316094 DOI: 10.3748/wjg.v21.i5.1518] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 08/28/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the distribution and expression of C-type natriuretic peptide (CNP)/natriuretic peptide receptor B (NPR-B) in the rectum of a rodent depression model and the interventional effect of Xiaoyaosan (XYS).
METHODS: Male rats (n = 45) of clean grade (200 ± 20 g) were divided into five groups after one week of adaptive feeding: primary control, depression model, low dose XYS, middle dose XYS, and high dose XYS. The animal experiment continued for 3 wk. Primary controls were fed normally ad libitum. The rats of all other groups were raised in solitary and exposed to classic chronic mild unpredictable stimulation each day. XYS groups were perfused intragastrically with low dose, middle dose, and high dose XYS one hour before stimulation. Primary control and depression model groups were perfused intragastrically with normal saline under similar conditions as the XYS groups. Three weeks later, all rats were sacrificed, and the expression levels of CNP and NPR-B in rectum tissues were analyzed by immunohistochemistry, real-time polymerase chain reaction, and Western blotting.
RESULTS: CNP and NPR-B were both expressed in the rectum tissues of all rats. However, the expression levels of CNP and NPR-B at both gene and protein levels in the depression model group were significantly higher when compared to the primary control group (n = 9; P < 0.01). XYS intervention markedly inhibited the expression levels of CNP and NPR-B in depressed rats. The expression levels of CNP and NPR-B in the high dose XYS group did not significantly differ from the expression levels in the primary control group. Additionally, the high and middle dose XYS groups (but not the low dose group) significantly exhibited lower CNP and NPR-B expression levels in the rectum tissues of the respectively treated rats compared to the untreated depression model cohort (n = 9; P < 0.01).
CONCLUSION: The CNP/NPR-B pathway is upregulated in the rectum of depressed rats and may be one mechanism for depression-associated digestive disorders. XYS antagonizes this pathway at least partially.
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MESH Headings
- Animals
- Antidepressive Agents/pharmacology
- Behavior, Animal/drug effects
- Depression/drug therapy
- Depression/genetics
- Depression/metabolism
- Depression/psychology
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drugs, Chinese Herbal/pharmacology
- Male
- Natriuretic Peptide, C-Type/genetics
- Natriuretic Peptide, C-Type/metabolism
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Receptors, Atrial Natriuretic Factor/drug effects
- Receptors, Atrial Natriuretic Factor/genetics
- Receptors, Atrial Natriuretic Factor/metabolism
- Rectum/drug effects
- Rectum/metabolism
- Signal Transduction/drug effects
- Time Factors
- Up-Regulation
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Abstract
Renal dysfunction (RD) in heart failure portends adverse outcomes and often limits aggressive medical and decongestive therapies. Despite the high prevalence in this population, not all forms of RD are prognostically or mechanistically equivalent: RD can result from irreversible nephron loss secondary to diabetic or hypertensive kidney disease or it can develop secondary to heart failure (HF) itself, i.e., the cardiorenal syndrome. Furthermore, filtration is only one aspect of renal performance such that significant renal impairment secondary to cardiorenal syndrome can exist despite a normal glomerular filtration rate. Renal biomarkers have the potential to inform some of the intricacies involved in accurately assessing cardiorenal interactions. This article discusses novel biomarkers for cardiorenal syndrome and their utility in the prognosis, diagnosis, and targeted treatment of heart failure-induced RD.
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Affiliation(s)
- Meredith A Brisco
- Division of Cardiology, Advanced Heart Failure and Cardiac Transplantation, Medical University of South Carolina, 25 Courtenay Drive, ART 7061, MSC 592, Charleston, SC, 29425-5920, USA,
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Moltzau LR, Aronsen JM, Meier S, Nguyen CHT, Hougen K, Ørstavik Ø, Sjaastad I, Christensen G, Skomedal T, Osnes JB, Levy FO, Qvigstad E. SERCA2 activity is involved in the CNP-mediated functional responses in failing rat myocardium. Br J Pharmacol 2014; 170:366-79. [PMID: 23808942 DOI: 10.1111/bph.12282] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 06/03/2013] [Accepted: 06/10/2013] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSES Myocardial C-type natriuretic peptide (CNP) levels are increased in heart failure. CNP can induce negative inotropic (NIR) and positive lusitropic responses (LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP-induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca(2+) ATPase2 (SERCA2) activity is essential for these responses. EXPERIMENTAL APPROACH Contractility, cGMP levels, Ca(2+) transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction. KEY RESULTS CNP increased cGMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban (PLB) Ser(16) and troponin I (TnI) Ser(23/24) phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/cGMP analogue (Rp-8-Br-Pet-cGMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca(2+) transient and increased SERCA2 activity in cardiomyocytes. The CNP-elicited NIR and LR were not affected by the L-type Ca(2+) channel activator BAY-K8644, but were abolished in the presence of isoprenaline (induces maximal activation of cAMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte-specific inactivation of the SERCA2 gene. CONCLUSIONS AND IMPLICATIONS We conclude that CNP-induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts.
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Affiliation(s)
- L R Moltzau
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; KG Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway
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Moltzau LR, Aronsen JM, Meier S, Skogestad J, Ørstavik Ø, Lothe GB, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Qvigstad E. Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle. J Pharmacol Exp Ther 2014; 350:681-90. [PMID: 25022512 DOI: 10.1124/jpet.114.214882] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
We previously found a negative inotropic (NIR) and positive lusitropic response (LR) to C-type natriuretic peptide (CNP) in the failing heart ventricle. In this study, we investigated and compared the functional responses to the natriuretic peptides (NPs), brain (BNP) and C-type natriuretic peptide (CNP), and relate them to cGMP regulation and effects on downstream targets. Experiments were conducted in left ventricular muscle strips and ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. As opposed to CNP, BNP did not cause an NIR or LR, despite increasing cGMP levels. The BNP-induced cGMP elevation was mainly and markedly regulated by phosphodiesterase (PDE) 2 and was only marginally increased by PDE3 or PDE5 inhibition. Combined PDE2, -3, and -5 inhibition failed to reveal any functional responses to BNP, despite an extensive cGMP elevation. BNP decreased, whereas CNP increased, the amplitude of the Ca(2+) transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca(2+) extrusion rate constant, or sarcoplasmatic reticulum Ca(2+) load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca(2+) current. Cyclic GMP elevations by BNP and CNP in cardiomyocytes were additive, and the presence of BNP did not alter the NIR to CNP or the CNP-induced PLB and TnI phosphorylation. However, a small increase in the LR to maximal CNP was observed in the presence of BNP. In conclusion, different responses to cGMP generated by BNP and CNP suggest different compartmentation of the cGMP signal and different roles of the two NPs in the failing heart.
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MESH Headings
- Animals
- Cells, Cultured
- Heart Failure/drug therapy
- Heart Failure/metabolism
- Heart Failure/pathology
- Male
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Natriuretic Peptide, Brain/metabolism
- Natriuretic Peptide, Brain/pharmacology
- Natriuretic Peptide, Brain/therapeutic use
- Natriuretic Peptide, C-Type/metabolism
- Natriuretic Peptide, C-Type/pharmacology
- Natriuretic Peptide, C-Type/therapeutic use
- Organ Culture Techniques
- Rats
- Rats, Wistar
- Ventricular Dysfunction, Left/drug therapy
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/pathology
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Affiliation(s)
- Lise Román Moltzau
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Jan Magnus Aronsen
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Silja Meier
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Jonas Skogestad
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Øivind Ørstavik
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Gustav B Lothe
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Ivar Sjaastad
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Tor Skomedal
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Jan-Bjørn Osnes
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Finn Olav Levy
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
| | - Eirik Qvigstad
- Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.)
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Lok DJ, Klip IJT, Voors AA, Lok SI, Bruggink-André de la Porte PW, Hillege HL, Jaarsma T, van Veldhuisen DJ, van der Meer P. Prognostic value of N-terminal pro C-type natriuretic peptide in heart failure patients with preserved and reduced ejection fraction. Eur J Heart Fail 2014; 16:958-66. [DOI: 10.1002/ejhf.140] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/05/2014] [Accepted: 05/06/2014] [Indexed: 11/06/2022] Open
Affiliation(s)
- Dirk J. Lok
- University Medical Center Groningen; Groningen The Netherlands
- Deventer Hospital; Deventer The Netherlands
| | | | | | - Sjoukje I. Lok
- University Medical Center Utrecht; Utrecht The Netherlands
| | | | - Hans L. Hillege
- University Medical Center Groningen; Groningen The Netherlands
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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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Moltzau LR, Meier S, Aronsen JM, Afzal F, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Qvigstad E. Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2014; 387:407-17. [PMID: 24424715 DOI: 10.1007/s00210-013-0953-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 12/19/2013] [Indexed: 11/29/2022]
Abstract
Recently, we showed C-type natriuretic peptide (CNP)-induced negative inotropic (NIR) and positive lusitropic response (LR) in failing rat heart. We wanted to study whether, and if so, how phosphodiesterases (PDEs) regulate CNP-induced cyclic 3',5'-guanosine monophosphate (cGMP) elevation and functional responses. Inotropic and lusitropic responses were measured in left ventricular muscle strips and cyclic nucleotide levels, PDE activity and phospholamban (PLB) and troponin I (TnI) phosphorylation were measured in ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. CNP-mediated increase in global cGMP was mainly regulated by PDE2, as reflected by a marked amplification of the cGMP increase during PDE2 inhibition and by a high PDE2 activity in cardiomyocytes. PDE3 inhibition, on the other hand, caused no significant cGMP increase by CNP. The functional consequences did not correspond to the changes of cGMP. PDE3 inhibition increased the potency of the CNP-induced NIR and LR, while PDE2 inhibition desensitized the CNP-induced NIR, but not LR. A role for PDE2 on the maximal LR and PDE5 on the maximal NIR to CNP was revealed in the presence of PDE3 inhibition. CNP increased PLB phosphorylation about 25- to 30-fold and tended to increase TnI phosphorylation about twofold. As a whole, CNP-induced functional responses were only modestly regulated by PDEs compared to the cAMP-mediated functional responses to β1-adrenoceptor stimulation, which are highly regulated by PDEs. There is a mismatch between the CNP-induced cGMP increase and functional responses. Global cGMP levels are mainly regulated by PDE2 after CNP stimulation, whereas the functional responses are modestly regulated by both PDE2 and PDE3, indicating cGMP compartmentation by PDEs affecting CNP-induced responses in failing hearts.
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Affiliation(s)
- Lise Román Moltzau
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, P.O. Box 1057 Blindern, N-0316, Oslo, Norway
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38
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Abstract
The concept of the heart as an endocrine organ arises from the observation that the atrial cardiomyocytes in the mammalian heart display a phenotype that is partly that of endocrine cells. Investigations carried out between 1971 and 1983 characterised, by virtue of its natriuretic properties, a polypeptide referred to atrial natriuretic factor (ANF). Another polypeptide isolated from brain in 1988, brain natriuretic peptide (BNP), was subsequently characterised as a second hormone produced by the mammalian heart atria. These peptides were associated with the maintenance of extracellular fluid volume and blood pressure. Later work demonstrated a plethora of other properties for ANF and BNP, now designated cardiac natriuretic peptides (cNPs). In addition to the cNPs, other polypeptide hormones are expressed in the heart that likely act upon the myocardium in a paracrine or autocrine fashion. These include the C-type natriuretic peptide, adrenomedullin, proadrenomedullin N-terminal peptide and endothelin-1. Expression and secretion of ANF and BNP are increased in various cardiovascular pathologies and their levels in blood are used in the diagnosis and prognosis of cardiovascular disease. In addition, therapeutic uses for these peptides or related substances have been found. In all, the discovery of the endocrine heart provided a shift from the classical functional paradigm of the heart that regarded this organ solely as a blood pump to one that regards this organ as self-regulating its workload humorally and that also influences the function of several other organs that control cardiovascular function.
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39
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Del Ry S, Cabiati M, Bianchi V, Storti S, Caselli C, Prescimone T, Clerico A, Saggese G, Giannessi D, Federico G. C-type natriuretic peptide plasma levels are reduced in obese adolescents. Peptides 2013; 50:50-4. [PMID: 24120372 DOI: 10.1016/j.peptides.2013.09.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 09/24/2013] [Accepted: 09/24/2013] [Indexed: 11/23/2022]
Abstract
The high prevalence of obesity in children may increase the magnitude of lifetime risk of cardiovascular disease (CD). At present, explicit data for recommending biomarkers as routine pre-clinical markers of CD in children are lacking. C-type natriuretic peptide (CNP) is assuming increasing importance in CD; in adults with heart failure, its plasma levels are related to clinical and functional disease severity. We have previously reported five different reference intervals for blood CNP as a function of age in healthy children; however, data on plasma CNP levels in obese children are still lacking. Aim of this study was to assess CNP levels in obese adolescents and verify whether they differ from healthy subjects. Plasma CNP was measured in 29 obese adolescents (age: 11.8 ± 0.4 years; BMI: 29.8 ± 0.82) by radioimmunoassay and compared with the reference values of healthy subjects. BNP was also measured. Both plasma CNP and BNP levels were significantly lower in the obese adolescents compared to the appropriate reference values (CNP: 3.4 ± 0.2 vs 13.6 ± 2.3 pg/ml, p<0.0001; BNP: 18.8 ± 2.6 vs 36.9 ± 5.5 pg/ml, p=0.003). There was no significant difference between CNP values in males and females. As reported in adults, we observed lower plasma CNP and BNP levels in obese children, suggesting a defective natriuretic peptide system in these patients. An altered regulation of production, clearance and function of natriuretic peptides, already operating in obese adolescents, may possibly contribute to the future development of CD. Thus, the availability of drugs promoting the action of natriuretic peptides may represent an attractive therapeutic option to prevent CD.
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Affiliation(s)
- S Del Ry
- CNR Institute of Clinical Physiology, CNR, Italy.
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40
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Recent advances on natriuretic peptide system: New promising therapeutic targets for the treatment of heart failure. Pharmacol Res 2013; 76:190-8. [DOI: 10.1016/j.phrs.2013.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 07/31/2013] [Accepted: 08/16/2013] [Indexed: 12/26/2022]
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Cabiati M, Sabatino L, Caruso R, Verde A, Caselli C, Prescimone T, Giannessi D, Del Ry S. C-type natriuretic peptide transcriptomic profiling increases in human leukocytes of patients with chronic heart failure as a function of clinical severity. Peptides 2013; 47:110-4. [PMID: 23911666 DOI: 10.1016/j.peptides.2013.07.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 07/18/2013] [Accepted: 07/18/2013] [Indexed: 11/22/2022]
Abstract
The aim of this study was to evaluate the transcriptomic profiling of C-type natriuretic peptide (CNP) and of its specific receptor, NPR-B in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and of HF patients (NYHA I-II, n=7; NYHA III-IV, n=13) with PAXgene Blood RNA Kit. Significantly higher levels of CNP mRNA expression were found in HF patients as a function of clinical severity (C=0.23±0.058, NYHA I-II=0.47±0.18, NYHA III-IV=2.58±0.71, p=0.005 C vs NYHA III-IV, p=0.017 NYHA I-II vs NYHA III-IV) and NPR-B transcript levels resulted down-regulated in HF patients with higher NYHA class (C=2.2±0.61, NYHA I-II=2.76±0.46, NYHA III-IV=0.29±0.13, p=0.001 C vs NYHA III-IV, p<0.0001 NYHA I-II vs NYHA III-IV). A significant negative correlation between CNP and NPR-B mRNA expression (r=0.5, p=0.03) was also observed. These results suggest a co-regulation of NPR-B and CNP expression supporting the relevance of this receptor in human disease characterized by a marked inflammatory/immune component and suggesting the possibility of manipulating inflammation via pharmacological agents selective for this receptor.
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Affiliation(s)
- M Cabiati
- CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy
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42
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Abstract
Heart failure is an important public health problem that is increasing in prevalence throughout the world. Not only is this condition common, but it is associated with significant morbidity and mortality as well as high costs to medical care systems. Vasodilator drugs help unload the heart and may have other effects that could benefit heart failure patients. Consequently, they have emerged as an important therapeutic approach for patients with this condition. Novel vasodilator therapies that are currently in development target new pathways, potentially giving clinicians alternate options for improving outcomes in this vulnerable population. This review focuses on investigational drugs that have the ability to dilate blood vessels amongst their therapeutic properties. These drugs include the natriuretic peptides that activate particulate guanylate cyclase, the novel agent cinaciguat that activates the soluble guanylate cyclase system, and finally a recombinant form of the naturally occurring vasodilating agent relaxin, a hormone that mediates many of the changes that allows the cardiovascular system to successfully adapt to pregnancy.
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Melaiu O, Facioni MS, Cabiati M, Caruso R, Giannessi D, Landi S, Gemignani F, Del Ry S. Characterization of novel 3'untranslated regions and related polymorphisms of the gene NPPC, encoding for the C-type natriuretic peptide. Peptides 2013; 44:93-9. [PMID: 23542429 DOI: 10.1016/j.peptides.2013.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 03/04/2013] [Accepted: 03/04/2013] [Indexed: 11/23/2022]
Abstract
Elevated plasmatic levels of C-type natriuretic peptide (CNP) were found in patients with chronic heart failure (CHF), but its use as sensitive and specific clinical bio-marker is still controversial. In fact, high levels of CNP were also observed in patients classified in low severity New York Heart Association (NYHA) classes. CNP is encoded by a gene poorly studied (NPPC, natriuretic-precursor peptide C), where the regulatory regions are not well defined and the role of single nucleotide polymorphisms (SNPs) poorly ascertained. In the present work, we focused on the characterization of the 3'untranslated region (3'UTR) of the gene, using Rapid Amplification of cDNA 3'-End (3' RACE), and we identified two novel transcript isoforms (L-3'UTR; S-3'UTR; accession number JF420840, HQ419060 respectively). Since it could be hypothesized that genetic variations could explain the observed inter-patients differences, we searched for novel SNPs, by the use of High Resolution Melting (HRM). The results showed a complete lack of genetic variations among our series of samples. Moreover, a preliminary evaluation, using literature information and bioinformatic prediction allowed us to predicted the putative relevant microRNAs binding to the novel 3'UTRs that could modulate the post-transcriptional regulation of NPPC and affect the plasmatic levels of CNP. We obtained 750 and 1024 predicted miRNAs targeting the S- and L-3'UTRs, respectively.
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Affiliation(s)
- O Melaiu
- Department of Biology, University of Pisa, 56126, Italy
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Prickett TCR, Olney RC, Cameron VA, Ellis MJ, Richards AM, Espiner EA. Impact of age, phenotype and cardio-renal function on plasma C-type and B-type natriuretic peptide forms in an adult population. Clin Endocrinol (Oxf) 2013; 78:783-9. [PMID: 22963390 DOI: 10.1111/cen.12035] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Revised: 06/14/2012] [Accepted: 09/03/2012] [Indexed: 11/28/2022]
Abstract
CONTEXT In contrast to the cardiac hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), variations in plasma concentrations of C-type natriuretic peptide (CNP) in healthy adults are ill-defined, limiting their clinical application. OBJECTIVE Our objective was to define the effect of age, phenotype (gender, height, BMI), and cardiac and renal function on plasma CNPs in an adults population without renal or cardiovascular disease. DESIGN AND SETTING This was a prospective cross-sectional observational study of adult volunteers, aged 21-80 years, randomly selected from the electoral roll. SUBJECTS AND METHODS Plasma CNP and its associated aminoterminal propeptide (NTproCNP) were measured in 258 subjects and related to age, gender, height and plasma creatinine. Subgroup analyses seeking associations with cardiac function (plasma BNP and NTproBNP) and bone turnover bone-specific alkaline phosphatase (bALP) were also determined. RESULTS Plasma concentrations of CNPs in men continued to decline from adolescent values to reach a nadir in the 5th decade after which values increased. Similar but less marked changes occurred in women. In both sexes, NTproCNP was inversely and independently correlated with height. In contrast to B-type natriuretic peptides (BNPs), NTproCNP was higher in men, significantly related to creatinine and positively related to bALP. CONCLUSIONS Gender- and age-specific changes affect CNPs in adults. Inverse associations of NTproCNP with adult height, positive correlation with creatinine - and in contrast to CNP - no association with BNP are further unique findings distinguishing NTproCNP, which need to be considered in future studies.
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Affiliation(s)
- T C R Prickett
- Department of Medicine, University of Otago, Christchurch, New Zealand.
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Zakeri R, Sangaralingham SJ, Sandberg SM, Heublein DM, Scott CG, Burnett JC. Urinary C-type natriuretic peptide: a new heart failure biomarker. JACC. HEART FAILURE 2013; 1:170-7. [PMID: 24244916 PMCID: PMC3825509 DOI: 10.1016/j.jchf.2012.12.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES This study was conducted to determine whether urinary excretion of C-type natriuretic peptide (CNP) is elevated in acute decompensated heart failure (ADHF) and whether elevated levels predict adverse outcomes. BACKGROUND Urinary CNP has been detected in patients with heart failure, but its clinical significance and prognostic utility, compared to established kidney injury biomarkers, in ADHF is unknown. METHODS We measured 24-h urinary excretion and concurrent plasma concentrations of CNP22, CNP53, and NT-CNP53 in 58 ADHF patients and 20 healthy control subjects. Urinary kidney injury molecule (KIM)-1 and neutrophil gelatinase–associated lipocalin (NGAL) and plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) were also measured. Mortality and all-cause rehospitalization/death were assessed over a follow-up of 1.5 ± 0.9 years. RESULTS ADHF patients had higher urinary excretion of all 3 CNP molecular forms than did controls. Plasma CNP22 and CNP53 were elevated in ADHF but showed limited correlation with urinary excretion, suggesting that mainly renal-derived CNP appears in urine. Plasma NT-proBNP and urinary KIM-1 were also elevated in ADHF (p < 0.0001); urinary NGAL was similar to that in controls. At 6 months, event-free survival values in ADHF patients were 86% for mortality and 59% for all-cause rehospitalization/death. On Cox regression analysis, urinary NT-CNP53 was the only predictor of mortality (hazard ratio: 1.7; 95% confidence interval: 1.1 to 2.4; p = 0.01) and all-cause rehospitalization/death (hazard ratio: 1.8; 95% confidence interval: 1.3 to 2.4; p = 0.0004), even after adjustment. Integrated discrimination analysis suggested that urinary NT-CNP53 combined with plasma NT-proBNP improved the prediction of adverse outcomes. CONCLUSIONS The findings from this study support the clinical utility of urinary CNP molecular forms. In ADHF, urinary NT-CNP53 correlated with prognosis, better predicted outcomes than did urinary NGAL and KIM-1, and improved the prognostic value of plasma NT-proBNP.
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Affiliation(s)
- Rosita Zakeri
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, U.S.A
| | - S. Jeson Sangaralingham
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, U.S.A
| | - Sharon M. Sandberg
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, U.S.A
| | - Denise M. Heublein
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, U.S.A
| | | | - John. C. Burnett
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, U.S.A
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Kuehnl A, Pelisek J, Bruckmeier M, Safi W, Eckstein HH. Comparative measurement of CNP and NT-proCNP in human blood samples: a methodological evaluation. J Negat Results Biomed 2013; 12:7. [PMID: 23547980 PMCID: PMC3621618 DOI: 10.1186/1477-5751-12-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 03/06/2013] [Indexed: 11/10/2022] Open
Abstract
Background C-type natriuretic peptide (CNP) has anti-inflammatory, anti-proliferative, and anti-migratory properties. During the past years, CNP has attained an increasing interest by many research groups, especially in the cardiovascular field. Nevertheless, still no reliable data exist on the difference of CNP concentration between serum and plasma samples. Also, the influence of delayed blood sample proceeding is unknown. The aim of this study was to investigate the difference of CNP and NT-proCNP concentrations between serum and plasma samples. In order to identify potential methodological bias, this study should also validate the stability of CNP and NT-proCNP in full blood samples stored at room temperature. Findings Triplets (serum, plasma, full blood) of fasting blood samples from 12 healthy male individuals were collected. Analysis of CNP and NT-proCNP concentration was performed immediately following sampling, and after 30 minutes or 2 hours of storage at room temperature. Mean serum concentrations at baseline were 0.997 ± 0.379 ng/ml for CNP and 58.5 ± 28.3 pg/ml for NT-proCNP. Furthermore, NT-proCNP concentration did not change significantly during the allotted time and did not differ between serum, plasma, and full blood samples. At baseline, concentrations of CNP were significantly different between samples containing either sodium-citrate or EDTA as a clotting inhibitor (1.933 ± 0.699 ng/ml vs. 0.991 ± 0.489 ng/ml, p = 0.001). Conclusions CNP and NT-proCNP are stable for at least two hours, even when sample processing is delayed or blood probes are stored at room temperature. NT-proCNP assay demonstrated more consistent and reliable data and should therefore be preferred for usage in clinical applications. Nevertheless, as recommended for ANP and BNP, immunoassays for CNP should also be standardized or harmonized in the future.
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Affiliation(s)
- Andreas Kuehnl
- Clinic for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Del Ry S. C-type natriuretic peptide: a new cardiac mediator. Peptides 2013; 40:93-8. [PMID: 23262354 DOI: 10.1016/j.peptides.2012.12.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 01/27/2023]
Abstract
Natriuretic peptides are endogenous hormones released by the heart in response to myocardial stretch and overload. While atrial and brain natriuretic peptides (ANP, BNP) were immediately considered cardiac hormones and their role was well-characterized and defined in predicting risk in cardiovascular disease, evidence indicating the role of C-type natriuretic peptide (CNP) in cardiovascular regulation was slow to emerge until about 8 years ago. Since then, considerable literature on CNP and the cardiovascular system has been published; the aim of this review is to examine current literature relating to CNP and cardiovascular disease, in particular its role in heart failure (HF) and myocardial infarction (MI). This review retraces the fundamental steps in research that led understanding the role of CNP in HF and MI; from increased CNP mRNA expression and plasmatic concentrations in humans and in animal models, to detection of CNP expression in cardiomyocytes, to its evaluation in human leukocytes. The traditional view of CNP as an endothelial peptide has been surpassed by the results of many studies published in recent years, and while its physiological role is still under investigation, information is now available regarding its contribution to cardiovascular function. Taken together, these observations suggest that CNP and its specific receptor, NPR-B, can play a very important role in regulating cardiac hypertrophy and remodeling, indicating NPR-B as a new potential drug target for the treatment of cardiovascular disease.
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Affiliation(s)
- S Del Ry
- CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy.
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Cabiati M, Sabatino L, Caruso R, Caselli C, Prescimone T, Giannessi D, Del Ry S. Gene expression of C-type natriuretic peptide and of its specific receptor NPR-B in human leukocytes of healthy and heart failure subjects. Peptides 2012; 37:240-6. [PMID: 22884919 DOI: 10.1016/j.peptides.2012.07.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 07/27/2012] [Accepted: 07/27/2012] [Indexed: 11/25/2022]
Abstract
C-type natriuretic peptide (CNP), a member of the family of natriuretic peptides, is synthesized and secreted from monocytes and macrophages that resulted to be a source of CNP at inflammatory sites. This suggests that special attention should be focused on the possible role of CNP in the immune system, in addition to its effects on the cardiovascular system. The aim of this study was to evaluate the possibility of measuring the mRNA expression of CNP and NPR-B, its specific receptor, in human whole blood samples of healthy (N; n=7) and heart failure (HF; n=7) subjects by Real-Time PCR (RT-PCR). Total RNA was extracted from leukocytes with QIAamp RNA Blood Kit and/or with PAXgene Blood RNA Kit. RT-PCR was performed and optimized for each primer. The experimental results were normalized with the three most stably expressed genes. CNP and NPR-B expression trend was similar in both fresh and frozen human whole blood. Significant higher levels of CNP and NPR-B mRNA expression were found in HF patients with respect to controls (CNP: N=1.23±0.33 vs. HF=6.54±2.09 p=0.027; NPR-B: N=0.85±0.23 vs. HF=5.31±1.98 p=0.04). A significant correlation between CNP and NPR-B (r=0.86, p<0.0001) was observed. Further studies are needed to clarify the pathophysiological properties of this peptide but the possibility to measure CNP and NPR-B mRNA expression in human leukocytes with a fast and easy procedure is a useful starting point for future investigation devoted to better understand the biomolecular processes associated to different diseases.
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Affiliation(s)
- M Cabiati
- CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy
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Chronic C-Type Natriuretic Peptide Infusion Attenuates Angiotensin II-Induced Myocardial Superoxide Production and Cardiac Remodeling. Int J Vasc Med 2012; 2012:246058. [PMID: 22848833 PMCID: PMC3405723 DOI: 10.1155/2012/246058] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 05/21/2012] [Accepted: 06/08/2012] [Indexed: 01/21/2023] Open
Abstract
Myocardial oxidative stress and inflammation are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived cardioprotective factor, although its effect on cardiac superoxide generation has not been investigated in vivo. This study tested the hypothesis that suppression of superoxide production contributes to the cardioprotective action of CNP. Angiotensin II (Ang II) or saline was continuously infused subcutaneously into mice using an osmotic minipump. Simultaneously with the initiation of Ang II treatment, mice were infused with CNP (0.05 μg/kg/min) or vehicle for 2 weeks. The heart weight to tibial length ratio was significantly increased by Ang II in vehicle-treated mice. Treatment with CNP decreased Ang II-induced cardiac hypertrophy without affecting systolic blood pressure. Echocardiography showed that CNP attenuated Ang II-induced increase in wall thickness, left ventricular dilatation, and decrease in fractional shortening. CNP reduced Ang II-induced increases in cardiomyocyte size and interstitial fibrosis and suppressed hypertrophic- and fibrosis-related gene expression. Finally, CNP decreased Ang II-induced cardiac superoxide production. These changes were accompanied by suppression of NOX4 gene expression. Our data indicate that treatment with CNP attenuated Ang II-induced cardiac hypertrophy, fibrosis, and contractile dysfunction which were accompanied by reduced cardiac superoxide production.
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C-type natriuretic peptide and its receptors in atherosclerotic plaques of the carotid artery of clinically asymptomatic patients. Eur J Vasc Endovasc Surg 2012; 43:649-54. [PMID: 22421372 DOI: 10.1016/j.ejvs.2012.02.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 02/14/2012] [Indexed: 11/23/2022]
Abstract
OBJECTIVES C-type natriuretic peptide (CNP) has anti-inflammatory, anti-proliferative and anti-migratory properties. No data exist on the presence of CNP in human atherosclerotic plaques of the carotid artery. Therefore, this study aimed to analyse qualitatively the distribution pattern and characteristics of CNP and its receptors in both, early and advanced human carotid plaques, as well as in stable and unstable lesions. In addition, the aim of this study was to evaluate CNP and its receptors as possible biomarkers to predict plaque stability in advanced lesions. METHODS Advanced carotid artery plaques of 40 asymptomatic patients (20 histologically stable and 20 histologically unstable) and early arteriosclerotic lesions of three patients were analysed. RESULTS Serum level of CNP was similar in patients with stable and unstable plaques (196 ± 19 pg ml(-1) vs. 198 ± 25 pg ml(-1), p = 0.948). Expression level of natriuretic peptide receptor 3 (NPR3) was significantly higher in unstable plaques compared to stable plaques (5.6 ± 1.8% vs. 1.7 ± 0.5%, p = 0.045). Expression levels of CNP and NPR2 were higher in unstable plaques but the differences were not statistically significant. The distribution pattern of CNP, NPR2 and NPR3 varied qualitatively between early and advanced carotid plaques. No relevant histological differences were observed with respect to plaque stability. CONCLUSIONS This study shows the presence of CNP and its receptors in atherosclerotic plaques of human carotid artery, with increased expression of NPR3 in histologically unstable plaques. In this study, serum CNP was not associated with histological plaque stability. In future, larger studies are required to further evaluate whether proteins of the CNP axis would be useful as biomarkers.
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