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1
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Huang H, Liu L, Liang Z, Wang Q, Li C, Huang Z, Zhao Z, Han W. C-type natriuretic peptide regulates lipid metabolism through a NPRB-PPAR pathway in the intramuscular and subcutaneous adipocytes in chickens. Sci Rep 2025; 15:13018. [PMID: 40234429 PMCID: PMC12000514 DOI: 10.1038/s41598-025-86433-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/10/2025] [Indexed: 04/17/2025] Open
Abstract
Natriuretic peptides (NPs) have an important role in lipid metabolism in skeletal muscle and adipose tissue in animals. C-type natriuretic peptide (CNP) is an important NP, but the molecular mechanisms that underlie its activity are not completely understood. Treatment of intramuscular fat (IMF) and subcutaneous fat (SCF) adipocytes with CNP led to decreased differentiation, promoted proliferation and lipolysis, and increased the expression of natriuretic peptide receptor B (NPRB) mRNA. Silencing natriuretic peptide C (NPPC) had the opposite results in IMF and SCF adipocytes. Transcriptome analysis found 665 differentially expressed genes (DEGs) in IMF adipocytes and 991 in SCF adipocytes. Seven genes in IMF adipocytes (FABP4, APOA1, ACOX2, ADIPOQ, CD36, FABP5, and LPL) and eight genes in SCF adipocytes (ACOX3, ACSL1, APOA1, CPT1A, CPT2, FABP4, PDPK1 and PPARα) are related to fat metabolism. Fifteen genes were found to be enriched in the peroxisome proliferator-activated receptor (PPAR) pathway. Integrated analysis identified 113 intersection genes in IMF and SCF adipocytes, two of which (APOA1 and FABP4) were enriched in the PPAR pathway. In conclusion, CNP may regulated lipid metabolism through the NPRB-PPAR pathway in both IMF and SCF adipocytes, FABP4 and APOA1 may be the key genes that mediated CNP regulation of fat deposition.
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Affiliation(s)
- Huayun Huang
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Longzhou Liu
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Zhong Liang
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Qianbao Wang
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Chunmiao Li
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Zhengyang Huang
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China
| | - Zhenhua Zhao
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China.
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China.
| | - Wei Han
- Institute of Poultry Science, Chinese Academy of Agriculture Sciences, 225125, Jiangsu, P. R. China.
- College of Animal Science, Yangtze University, Jingzhou, 8060550, P. R. China.
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2
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Wang L, Tang Y, Buckley AF, Spurney RF. Podocyte specific knockout of the natriuretic peptide clearance receptor is podocyte protective in focal segmental glomerulosclerosis. PLoS One 2025; 20:e0319424. [PMID: 40063586 PMCID: PMC11892885 DOI: 10.1371/journal.pone.0319424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/31/2025] [Indexed: 05/13/2025] Open
Abstract
Natriuretic peptides (NPs) bind to glomerular podocytes and attenuate glomerular injury. The beneficial effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which is highly expressed in podocytes. To determine if inhibiting NPRC is podocyte protective, we examined the effects of deleting NPRC in both cultured podocytes and in vivo. We found that: 1.Both atrial NP and C-type NP inhibit podocyte apoptosis in cultured podocytes, but these podocyte protective effects are significantly attenuated in cells expressing NPRC, and 2. Atrial NP was significantly more effective than CNP at inhibiting the apoptotic response. Consistent with the protective actions of NPs, podocyte specific knockout of NPRC reduced albuminuria, glomerular sclerosis and tubulointerstitial inflammation in a mouse model of focal segmental glomerulosclerosis. These beneficial actions were associated with: 1. Decreased expression of the myofibroblast marker alpha-smooth muscle actin, 2. Reduced expression of the extracellular matrix proteins collagen 4-alpha-1 and fibronectin, and 3. Preserved expression of the podocyte proteins nephrin and podocin. Inhibiting NP clearance may be a useful therapeutic approach to treat glomerular diseases.
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MESH Headings
- Podocytes/metabolism
- Podocytes/pathology
- Podocytes/drug effects
- Animals
- Glomerulosclerosis, Focal Segmental/pathology
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/genetics
- Receptors, Atrial Natriuretic Factor/genetics
- Receptors, Atrial Natriuretic Factor/metabolism
- Receptors, Atrial Natriuretic Factor/deficiency
- Mice
- Apoptosis/drug effects
- Mice, Knockout
- Natriuretic Peptide, C-Type/pharmacology
- Natriuretic Peptide, C-Type/metabolism
- Disease Models, Animal
- Membrane Proteins/metabolism
- Albuminuria/genetics
- Male
- Intracellular Signaling Peptides and Proteins
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Affiliation(s)
- Liming Wang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Yuping Tang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
| | - Anne F. Buckley
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Robert F. Spurney
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States of America
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3
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Nakamori T, Komatsuzawa I, Iwata U, Makita A, Kagiya G, Fujitani K, Kitaguchi T, Tsuboi T, Ohki-Hamazaki H. The role of osteocrin in memory formation during early learning, as revealed by visual imprinting in chicks. iScience 2024; 27:111195. [PMID: 39600306 PMCID: PMC11591550 DOI: 10.1016/j.isci.2024.111195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/17/2024] [Accepted: 10/15/2024] [Indexed: 11/29/2024] Open
Abstract
Osteocrin (OSTN) is structurally associated with natriuretic peptides. Its expression in the brain, which has only been recognized in anthropoid primates, is induced by sensory stimuli and regulates the activity-dependent dendritic growth of neurons. However, details on the signaling mechanisms of OSTN and its function in plastic changes during learning and memory have yet to be elucidated. We found that OSTN was expressed in the cortical region of the chicken brain. The injection of chicken OSTN (chOSTN) after imprinting training prolonged the memory retention for the imprinting stimulus. Conversely, a reduction in the OSTN receptor chNPR3 inhibited memory retention. The memory retention was positively correlated with a high level of chOSTN and fewer neurites in the cortical region. In conclusion, OSTN-NPR3 signaling promoted memory consolidation and/or retention by regulating neurite branching during childhood.
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Affiliation(s)
- Tomoharu Nakamori
- College of Liberal Arts and Sciences, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Izumi Komatsuzawa
- College of Liberal Arts and Sciences, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Umi Iwata
- College of Liberal Arts and Sciences, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Ami Makita
- College of Liberal Arts and Sciences, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Go Kagiya
- School of Allied Health Sciences, and Regenerative Medicine and Cell Design Research Facility, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - Kazuko Fujitani
- Gene Analysis Center, School of Medicine, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - Tetsuya Kitaguchi
- Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan
| | - Takashi Tsuboi
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Meguro-ku, Tokyo 153-8902, Japan
| | - Hiroko Ohki-Hamazaki
- College of Liberal Arts and Sciences, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
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Lee HS, Kim HY, Ahn YM, Cho KW. Herbal medicine Oryeongsan (Wulingsan): Cardio-renal effects via modulation of renin-angiotensin system and atrial natriuretic peptide system. Integr Med Res 2024; 13:101066. [PMID: 39247397 PMCID: PMC11378099 DOI: 10.1016/j.imr.2024.101066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/06/2024] [Accepted: 06/20/2024] [Indexed: 09/10/2024] Open
Abstract
Background Oryeongsan (Wulingsan, Goreisan) has long been used for the treatment of impaired body fluid metabolism. However, the action mechanisms have not been clearly defined. Recently, effects of Oryeongsan on the body fluid and Na+ metabolism and the action mechanisms have been shown more clearly. The present review focuses on the recent findings on the effects of Oryeongsan in the cardio-renal system in relation with body fluid metabolism and action mechanisms leading to a decrease in blood pressure in animal models of hypertension. Methods The new and recent findings were searched by using searching systems including PubMed-NCBI and Google-Scholar. Results Oryeongsan induced an increase in glomerular filtration rate, and natriuresis and diuresis with a decreased osmolality and resulted in a contraction of the body fluid and Na+ balance. These findings were associated with a suppression of abundance of Na+-H +-exchanger isoform 3 expression and V2 receptor/aquaporin2 water channel signaling pathway in the kidney. Further, treatment with Oryeongsan accentuated atrial natriuretic peptide secretion in the atria from spontaneously hypertensive rats in which the secretion was suppressed. In addition, Oryeongsan ameliorated impaired vasodilation in spontaneously hypertensive rats. Conclusion The effects of Oryeongsan in the kidney, atria, and vessel were accompanied by a suppression of AT1 receptor and concurrent accentuation of abundance of AT2/Mas receptors expression and modulation of the natriuretic peptide system in these organs from hypertensive rats. The review shows multiple sites of action of Oryeongsan and mechanisms involved in the regulation of volume and pressure homeostasis in the body.
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Affiliation(s)
- Ho Sub Lee
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
| | - Hye Yoom Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
| | - You Mee Ahn
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Kyung Woo Cho
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
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5
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Scott NJA, Prickett TCR, Charles CJ, Espiner EA, Richards AM, Rademaker MT. Haemodynamic, hormonal and renal actions of osteocrin in normal sheep. Exp Physiol 2024; 109:1305-1316. [PMID: 38890799 PMCID: PMC11291853 DOI: 10.1113/ep091826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024]
Abstract
Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.
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Affiliation(s)
- Nicola J. A. Scott
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
| | - Timothy C. R. Prickett
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
| | - Christopher J. Charles
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
| | - Eric A. Espiner
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
| | - A. Mark Richards
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
- Cardiovascular Research Institute, National University Health SystemsCentre for Translational MedicineSingaporeSingapore
| | - Miriam T. Rademaker
- Department of Medicine, Christchurch Heart InstituteUniversity of Otago ChristchurchChristchurchNew Zealand
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6
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Ogawa H, Kodama M. Structural insight into hormone recognition by the natriuretic peptide receptor-A. FEBS J 2024; 291:2273-2286. [PMID: 38437249 DOI: 10.1111/febs.17104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 11/21/2023] [Accepted: 02/16/2024] [Indexed: 03/06/2024]
Abstract
Atrial natriuretic peptide (ANP) plays a central role in the regulation of blood pressure and volume. ANP activities are mediated by natriuretic peptide receptor-A (NPR-A), a single-pass transmembrane receptor harboring intrinsic guanylate cyclase activity. This study investigated the mechanism underlying NPR-A-dependent hormone recognition through the determination of the crystal structures of the NPR-A extracellular hormone-binding domain complexed with full-length ANP, truncated mutants of ANP, and dendroaspis natriuretic peptide (DNP) isolated from the venom of the green Mamba snake, Dendroaspis angusticeps. The bound peptides possessed pseudo-two-fold symmetry, despite the lack of two-fold symmetry in the primary sequences, which enabled the tight coupling of the peptide to the receptor, and evidently contributes to guanylyl cyclase activity. The binding of DNP to the NPR-A was essentially identical to that of ANP; however, the affinity of DNP for NPR-A was higher than that of ANP owing to the additional interactions between distinctive sequences in the DNP and NPR-A. Consequently, our findings provide valuable insights that can be applied to the development of novel agonists for the treatment of various human diseases.
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Affiliation(s)
- Haruo Ogawa
- Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Masami Kodama
- Department of Bio-informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Japan
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7
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Nasab Mehrabi E, Toupchi‐Khosroshahi V, Athari SS. Relationship of atrial fibrillation and N terminal pro brain natriuretic peptide in heart failure patients. ESC Heart Fail 2023; 10:3250-3257. [PMID: 37776150 PMCID: PMC10682909 DOI: 10.1002/ehf2.14542] [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: 12/20/2022] [Revised: 07/15/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023] Open
Abstract
N terminal pro brain natriuretic peptide (NT-proBNP) plays an important role in the diagnosis and prognosis of heart failure (HF). The plasma level of NT-proBNP in atrial fibrillation (AF) patients was higher than of sinus rhythm patients. In HF, NT-proBNP levels are affected by the concomitant presence of AF, making it difficult to distinguish between HF and AF in patients with elevated NT-proBNP. Several other diseases, such as renal failure and pulmonary embolism, are known to further increase NT-proBNP levels in patients with concomitant HF. Therefore, NT-proBNP is a sensitive but non-specific marker for the detection of HF. AF is very important in this regard because among patients with HF regardless of ejection fraction, symptoms such as shortness of breath and atrial enlargement develop and can mimic HF. In the present study, we investigated whether the prognostic value of natriuretic peptides in HF holds true for patients with concomitant AF.
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Affiliation(s)
- Entezar Nasab Mehrabi
- Department of Cardiology, School of Medicine, Tehran Heart CenterTehran University of Medical SciencesTehranIran
- Department of Cardiology, School of MedicineValiasr Hospital, Zanjan University of Medical SciencesZanjanIran
| | - Vahid Toupchi‐Khosroshahi
- Department of Cardiology, School of MedicineValiasr Hospital, Zanjan University of Medical SciencesZanjanIran
- Department of Cardiology, School of MedicineAyatollah Mousavi Hospital, Zanjan University of Medical SciencesZanjanIran
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8
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Liu D, Ceddia RP, Zhang W, Shi F, Fang H, Collins S. Discovery of another mechanism for the inhibition of particulate guanylyl cyclases by the natriuretic peptide clearance receptor. Proc Natl Acad Sci U S A 2023; 120:e2307882120. [PMID: 37399424 PMCID: PMC10334801 DOI: 10.1073/pnas.2307882120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 05/30/2023] [Indexed: 07/05/2023] Open
Abstract
The cardiac natriuretic peptides (NPs) control pivotal physiological actions such as fluid and electrolyte balance, cardiovascular homeostasis, and adipose tissue metabolism by activating their receptor enzymes [natriuretic peptide receptor-A (NPRA) and natriuretic peptide receptor-B (NPRB)]. These receptors are homodimers that generate intracellular cyclic guanosine monophosphate (cGMP). The natriuretic peptide receptor-C (NPRC), nicknamed the clearance receptor, lacks a guanylyl cyclase domain; instead, it can bind the NPs to internalize and degrade them. The conventional paradigm is that by competing for and internalizing NPs, NPRC blunts the ability of NPs to signal through NPRA and NPRB. Here we show another previously unknown mechanism by which NPRC can interfere with the cGMP signaling function of the NP receptors. By forming a heterodimer with monomeric NPRA or NPRB, NPRC can prevent the formation of a functional guanylyl cyclase domain and thereby suppress cGMP production in a cell-autonomous manner.
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Affiliation(s)
- Dianxin Liu
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, NashvilleTN37232
| | - Ryan P. Ceddia
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, NashvilleTN37232
| | - Wei Zhang
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, NashvilleTN37232
| | - Fubiao Shi
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, NashvilleTN37232
| | - Huafeng Fang
- Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL32827
| | - Sheila Collins
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, NashvilleTN37232
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN37232
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9
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Honigberg MC, Truong B, Khan RR, Xiao B, Bhatta L, Vy HMT, Guerrero RF, Schuermans A, Selvaraj MS, Patel AP, Koyama S, Cho SMJ, Vellarikkal SK, Trinder M, Urbut SM, Gray KJ, Brumpton BM, Patil S, Zöllner S, Antopia MC, Saxena R, Nadkarni GN, Do R, Yan Q, Pe'er I, Verma SS, Gupta RM, Haas DM, Martin HC, van Heel DA, Laisk T, Natarajan P. Polygenic prediction of preeclampsia and gestational hypertension. Nat Med 2023; 29:1540-1549. [PMID: 37248299 PMCID: PMC10330886 DOI: 10.1038/s41591-023-02374-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 04/26/2023] [Indexed: 05/31/2023]
Abstract
Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.
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Affiliation(s)
- Michael C Honigberg
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
| | - Buu Truong
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Raiyan R Khan
- Department of Computer Science, Columbia University, New York, NY, USA
| | - Brenda Xiao
- University of Pennsylvania, Philadelphia, PA, USA
| | - Laxmi Bhatta
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
| | - Ha My T Vy
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rafael F Guerrero
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Art Schuermans
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Faculty of Medicine, KU Leuven, Leuven, Belgium
| | - Margaret Sunitha Selvaraj
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Aniruddh P Patel
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Satoshi Koyama
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - So Mi Jemma Cho
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Seoul, Republic of Korea
| | - Shamsudheen Karuthedath Vellarikkal
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Mark Trinder
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sarah M Urbut
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Kathryn J Gray
- Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Ben M Brumpton
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
| | - Snehal Patil
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Sebastian Zöllner
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Mariah C Antopia
- Department of Integrative Biology, University of Texas at San Antonio, San Antonio, TX, USA
| | - Richa Saxena
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Girish N Nadkarni
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Qi Yan
- Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
| | - Itsik Pe'er
- Department of Computer Science, Columbia University, New York, NY, USA
| | | | - Rajat M Gupta
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - David M Haas
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Hilary C Martin
- Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK
| | - David A van Heel
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Triin Laisk
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Pradeep Natarajan
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
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10
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Wang L, Tang Y, Herman MA, Spurney RF. Pharmacologic blockade of the natriuretic peptide clearance receptor promotes weight loss and enhances insulin sensitivity in type 2 diabetes. Transl Res 2023; 255:140-151. [PMID: 36563959 PMCID: PMC10441142 DOI: 10.1016/j.trsl.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/30/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. To determine if pharmacologic blockade of NPRC enhanced the beneficial metabolic actions of NPs in type 2 diabetes, we blocked NP clearance in a mouse model of type 2 diabetes using the specific NPRC ligand ANP(4-23). We found that treatment with ANP(4-23) caused a significant decrease in body weight by increasing energy expenditure and reducing fat mass without a change in lean body mass. The decrease in fat mass was associated with a significant improvement in insulin sensitivity and reduced serum insulin levels. These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.
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Affiliation(s)
- Liming Wang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina
| | - Yuping Tang
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina
| | - Mark A Herman
- Division of Endocrinology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina; Duke Molecular Physiology Institute, Durham, North Carolina
| | - Robert F Spurney
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina.
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11
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Zheng H, Patel TA, Liu X, Patel KP. C-type natriuretic peptide (CNP) in the paraventricular nucleus-mediated renal sympatho-inhibition. Front Physiol 2023; 14:1162699. [PMID: 37082246 PMCID: PMC10110992 DOI: 10.3389/fphys.2023.1162699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
Volume reflex produces sympatho-inhibition that is mediated by the hypothalamic paraventricular nucleus (PVN). However, the mechanisms for the sympatho-inhibitory role of the PVN and the neurochemical factors involved remain to be identified. In this study, we proposed C-type natriuretic peptide (CNP) as a potential mediator of this sympatho-inhibition within the PVN. Microinjection of CNP (1.0 μg) into the PVN significantly decreased renal sympathetic nerve activity (RSNA) (-25.8% ± 1.8% vs. -3.6% ± 1.5%), mean arterial pressure (-15.0 ± 1.9 vs. -0.1 ± 0.9 mmHg) and heart rate (-23.6 ± 3.5 vs. -0.3 ± 0.9 beats/min) compared with microinjection of vehicle. Picoinjection of CNP significantly decreased the basal discharge of extracellular single-unit recordings in 5/6 (83%) rostral ventrolateral medulla (RVLM)-projecting PVN neurons and in 6/13 (46%) of the neurons that were not antidromically activated from the RVLM. We also observed that natriuretic peptide receptor type C (NPR-C) was present on the RVLM projecting PVN neurons detected by dual-labeling with retrograde tracer. Prior NPR-C siRNA microinjection into the PVN significantly blunted the decrease in RSNA to CNP microinjections into the PVN. Volume expansion-mediated reduction in RSNA was significantly blunted by prior administration of NPR-C siRNA into the PVN. These results suggest a potential role for CNP within the PVN in regulating RSNA, specifically under physiological conditions of alterations in fluid balance.
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Affiliation(s)
- Hong Zheng
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, United States
| | - Tapan A. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Xuefei Liu
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, United States
| | - Kaushik P. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
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12
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Jehle A, Garaschuk O. The Interplay between cGMP and Calcium Signaling in Alzheimer's Disease. Int J Mol Sci 2022; 23:7048. [PMID: 35806059 PMCID: PMC9266933 DOI: 10.3390/ijms23137048] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/31/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer's disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca2+ signaling, e.g., causing changes in cGMP-mediated Ca2+ release from the intracellular stores as well as Ca2+-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca2+ signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer's disease.
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Affiliation(s)
| | - Olga Garaschuk
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany;
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13
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Smith R, Perez-Ternero C, Conole D, Martin C, Myers SH, Hobbs AJ, Selwood DL. A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C. J Med Chem 2022; 65:5495-5513. [PMID: 35333039 PMCID: PMC9014859 DOI: 10.1021/acs.jmedchem.1c01974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure-activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound 1 was identified as a potent agonist (EC50 ∼ 1 μM) with promising in vivo pharmacokinetic properties.
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Affiliation(s)
- Robert
J. Smith
- Wolfson
Institute for Biomedical Research, University
College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
| | - Cristina Perez-Ternero
- William
Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
| | - Daniel Conole
- Wolfson
Institute for Biomedical Research, University
College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
| | - Capucine Martin
- William
Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
| | - Samuel H. Myers
- Wolfson
Institute for Biomedical Research, University
College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
| | - Adrian J. Hobbs
- William
Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
| | - David L. Selwood
- Wolfson
Institute for Biomedical Research, University
College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
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14
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Abstract
The global mortality, morbidity, and healthcare costs associated with cardiometabolic disease, including obesity, diabetes, hypertension, and dyslipidemia, are substantial and represent an expanding unmet medical need. Herein, we have identified a physiological role for C-type natriuretic peptide (CNP) in regulating key processes, including thermogenesis and adipogenesis, which combine to coordinate metabolic function and prevent the development of cardiometabolic disorders. This protective mechanism, which is in part mediated via an autocrine action of CNP on adipocytes, is underpinned by activation of cognate natriuretic peptide receptors (NPR)-B and NPR-C. This mechanism advances the fundamental understanding of energy homeostasis and glucose handling and offers the promise of improving the treatment of cardiometabolic disease. Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders.
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15
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Meng QT, Liu XY, Liu XT, Liu J, Munanairi A, Barry DM, Liu B, Jin H, Sun Y, Yang Q, Gao F, Wan L, Peng J, Jin JH, Shen KF, Kim R, Yin J, Tao A, Chen ZF. BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk. eLife 2021; 10:71689. [PMID: 34919054 PMCID: PMC8789279 DOI: 10.7554/elife.71689] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/16/2021] [Indexed: 11/13/2022] Open
Abstract
Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCβ-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice. An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.
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Affiliation(s)
- Qing-Tao Meng
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Xian-Yu Liu
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Xue-Ting Liu
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Juan Liu
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Admire Munanairi
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Devin M Barry
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Benlong Liu
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Hua Jin
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Yu Sun
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Qianyi Yang
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Fang Gao
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Li Wan
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Jiahang Peng
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Jin-Hua Jin
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Kai-Feng Shen
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Ray Kim
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Jun Yin
- Center for the Study of Itch and Sensory Disorders, Washington University in St. Louis, St Louis, United States
| | - Ailin Tao
- Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhou-Feng Chen
- Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
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16
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Mascolo A, di Mauro G, Cappetta D, De Angelis A, Torella D, Urbanek K, Berrino L, Nicoletti GF, Capuano A, Rossi F. Current and future therapeutic perspective in chronic heart failure. Pharmacol Res 2021; 175:106035. [PMID: 34915125 DOI: 10.1016/j.phrs.2021.106035] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022]
Abstract
The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.
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Affiliation(s)
- Annamaria Mascolo
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy.
| | - Gabriella di Mauro
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Donato Cappetta
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Konrad Urbanek
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Liberato Berrino
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Giovanni Francesco Nicoletti
- Plastic Surgery Unit, University of Campania "Luigi Vanvitelli, Multidisciplinary Department of Medical Surgical and Dental Sciences, Napoli, Italy
| | - Annalisa Capuano
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Francesco Rossi
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
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17
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Tegin G, Gao Y, Hamlyn JM, Clark BJ, El-Mallakh RS. Inhibition of endogenous ouabain by atrial natriuretic peptide is a guanylyl cyclase independent effect. PLoS One 2021; 16:e0260131. [PMID: 34793577 PMCID: PMC8601428 DOI: 10.1371/journal.pone.0260131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 11/03/2021] [Indexed: 12/15/2022] Open
Abstract
Background Endogenous ouabain (EO) and atrial natriuretic peptide (ANP) are important in regulation of sodium and fluid balance. There is indirect evidence that ANP may be involved in the regulation of endogenous cardenolides. Methods H295R are human adrenocortical cells known to release EO. Cells were treated with ANP at physiologic concentrations or vehicle (0.1% DMSO), with or without guanylyl cyclase inhibitor 1,2,4 oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cyclic guanosine monophosphate (cGMP), the intracellular second messenger of ANP, was measured by a chemiluminescent immunoassay and EO was measured by radioimmunoassay of C18 extracted samples. Results EO secretion is inhibited by ANP treatment, with the most prolonged inhibition (90 min vs ≤ 60 min) occurring at physiologic ANP concentrations (50 pg/mL). Inhibition of guanylyl cyclase with ODQ, also reduces EO secretion. The inhibitory effects on EO release in response to cotreatment with ANP and ODQ appeared to be additive. Conclusions ANP inhibits basal EO secretion, and it is unlikely that this is mediated through ANP-A or ANP-B receptors (the most common natriuretic peptide receptors) or their cGMP second messenger; the underlying mechanisms involved are not revealed in the current studies. The role of ANP in the control of EO synthesis and secretion in vivo requires further investigation.
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Affiliation(s)
- Gulay Tegin
- Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, Kentucky, United States of America
| | - Yonglin Gao
- Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, Kentucky, United States of America
| | - John M. Hamlyn
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, Mississippi, United States of America
| | - Barbara J. Clark
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, United States of America
| | - Rif S. El-Mallakh
- Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, Kentucky, United States of America
- * E-mail:
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18
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Wang L, Tang Y, Buckley AF, Spurney RF. Blockade of the natriuretic peptide clearance receptor attenuates proteinuria in a mouse model of focal segmental glomerulosclerosis. Physiol Rep 2021; 9:e15095. [PMID: 34755480 PMCID: PMC8578888 DOI: 10.14814/phy2.15095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 12/31/2022] Open
Abstract
Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide-induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4-23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non-TG animals. We found that natriuretic peptides protected cultured podocytes from PAN-induced apoptosis, and that ANP(4-23) enhanced natriuretic peptide-induced cGMP generation in vivo. PAN-induced heavy proteinuria in vehicle-treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4-23). Treatment with ANP(4-23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4-23)-treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively.
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Affiliation(s)
- Liming Wang
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
| | - Yuping Tang
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
| | - Anne F. Buckley
- Department of PathologyDuke University Medical CenterDurhamNorth CarolinaUSA
| | - Robert F. Spurney
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
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19
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Pandey KN. Molecular Signaling Mechanisms and Function of Natriuretic Peptide Receptor-A in the Pathophysiology of Cardiovascular Homeostasis. Front Physiol 2021; 12:693099. [PMID: 34489721 PMCID: PMC8416980 DOI: 10.3389/fphys.2021.693099] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
The discovery of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) and their cognate receptors has greatly increased our knowledge of the control of hypertension and cardiovascular homeostasis. ANP and BNP are potent endogenous hypotensive hormones that elicit natriuretic, diuretic, vasorelaxant, antihypertrophic, antiproliferative, and antiinflammatory effects, largely directed toward the reduction of blood pressure (BP) and cardiovascular diseases (CVDs). The principal receptor involved in the regulatory actions of ANP and BNP is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which produces the intracellular second messenger cGMP. Cellular, biochemical, molecular, genetic, and clinical studies have facilitated understanding of the functional roles of natriuretic peptides (NPs), as well as the functions of their receptors, and signaling mechanisms in CVDs. Transgenic and gene-targeting (gene-knockout and gene-duplication) strategies have produced genetically altered novel mouse models and have advanced our knowledge of the importance of NPs and their receptors at physiological and pathophysiological levels in both normal and disease states. The current review describes the past and recent research on the cellular, molecular, genetic mechanisms and functional roles of the ANP-BNP/NPRA system in the physiology and pathophysiology of cardiovascular homeostasis as well as clinical and diagnostic markers of cardiac disorders and heart failure. However, the therapeutic potentials of NPs and their receptors for the diagnosis and treatment of cardiovascular diseases, including hypertension, heart failure, and stroke have just begun to be expanded. More in-depth investigations are needed in this field to extend the therapeutic use of NPs and their receptors to treat and prevent CVDs.
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Affiliation(s)
- Kailash N. Pandey
- Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA, United States
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Hall EJ, Pal S, Glennon MS, Shridhar P, Satterfield SL, Weber B, Zhang Q, Salama G, Lal H, Becker JR. Cardiac natriuretic peptide deficiency sensitizes the heart to stress induced ventricular arrhythmias via impaired CREB signaling. Cardiovasc Res 2021; 118:2124-2138. [PMID: 34329394 DOI: 10.1093/cvr/cvab257] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/28/2021] [Indexed: 11/14/2022] Open
Abstract
AIMS The cardiac natriuretic peptides (atrial natriuretic peptide [ANP] and B-type natriuretic peptide [BNP]) are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities. METHODS AND RESULTS We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP deficient (Nppa-/-) or BNP deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human derived induced pluripotent stem cell cardiomyocytes (iPS-CM). In the unstressed state, both ANP and BNP deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodeling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild type hearts to stress induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen activated protein kinase (p38 MAPK) signaling cascade. CONCLUSIONS Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signaling which sensitizes the heart to stress induced ventricular arrhythmias. TRANSLATIONAL PERSPECTIVE Our study found that ANP or BNP deficiency leads to increased sudden death and ventricular arrhythmias after acute myocardial stress in murine models. We discovered that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels and uncovered a unique role for these peptides in regulating cardiomyocyte p38 MAPK and CREB signaling through a cGMP-PKG1 pathway. Importantly, this signaling pathway was conserved in human cardiomyocytes. This study provides mechanistic insight into how modulating natriuretic peptide levels in human heart failure patients reduces sudden death and mortality.
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Affiliation(s)
- Eric J Hall
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Soumojit Pal
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Michael S Glennon
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Puneeth Shridhar
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sidney L Satterfield
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Beth Weber
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Qinkun Zhang
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA
| | - Guy Salama
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Hind Lal
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA
| | - Jason R Becker
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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21
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Abstract
Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
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22
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Kato J. Natriuretic peptides and neprilysin inhibition in hypertension and hypertensive organ damage. Peptides 2020; 132:170352. [PMID: 32610060 DOI: 10.1016/j.peptides.2020.170352] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 01/22/2023]
Abstract
The family of natriuretic peptides (NPs) discovered in mammalian tissues including cardiac atrium and brain consists of three members, namely, atrial, B- and C-type natriuretic peptides (ANP, BNP, CNP). Since the discovery, basic and clinical studies have been vigorously performed to explore the biological functions and pathophysiological roles of NPs in a wide range of diseases including hypertension and heart failure. These studies revealed that ANP and BNP are hormones secreted from the heart into the blood stream in response to pre- or after-load, counteracting blood pressure (BP) elevation and fluid retention through specific receptors. Meanwhile, CNP was found to be produced by the vascular endothelium, acting as a local mediator potentially serving protective functions for the blood vessels. Because NPs not only exert blood pressure lowering actions but also alleviate hypertensive organ damage, attempts have been made to develop therapeutic agents for hypertension by utilizing this family of NPs. One strategy is to inhibit neprilysin, an enzyme degrading NPs, thereby enhancing the actions of endogenous peptides. Recently, a dual inhibitor of angiotensin receptor-neprilysin was approved for heart failure, and neprilysin inhibition has also been shown to be beneficial in treating patients with hypertension. This review summarizes the roles of NPs in regulating BP, with special references to hypertension and hypertensive organ damage, and discusses the therapeutic implications of neprilysin inhibition.
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Affiliation(s)
- Johji Kato
- Frontier Science Research Center, University of Miyazaki Faculty of Medicine, Cardiovascular Medicine, University of Miyazaki Hospital, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
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23
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Zhao J, Pei L. Cardiac Endocrinology: Heart-Derived Hormones in Physiology and Disease. ACTA ACUST UNITED AC 2020; 5:949-960. [PMID: 33015416 PMCID: PMC7524786 DOI: 10.1016/j.jacbts.2020.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/11/2022]
Abstract
The heart plays a central role in the circulatory system and provides essential oxygen, nutrients, and growth factors to the whole organism. The heart can synthesize and secrete endocrine signals to communicate with distant target organs. Studies of long-known and recently discovered heart-derived hormones highlight a shared theme and reveal a unified mechanism of heart-derived hormones in coordinating cardiac function and target organ biology. This paper reviews the biochemistry, signaling, function, regulation, and clinical significance of representative heart-derived hormones, with a focus on the cardiovascular system. This review also discusses important and exciting questions that will advance the field of cardiac endocrinology.
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Key Words
- ANP, atrial natriuretic peptide
- ActR, activin receptor
- BNP, brain natriuretic peptide
- CNP, C-type natriuretic peptide
- FGF, fibroblast growth factor
- FSTL, follistatin-like
- GDF, growth differentiation factor
- GDF15
- GFRAL, GDNF family receptor α-like
- NPR, natriuretic peptide receptors
- PCSK, proprotein convertase subtilisin/kexin type
- ST2, suppression of tumorigenesis-2
- TGF, transforming growth factor
- cardiac endocrinology
- heart
- heart-derived hormones
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Affiliation(s)
- Juanjuan Zhao
- Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Liming Pei
- Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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24
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Ceddia RP, Collins S. A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure. Clin Sci (Lond) 2020; 134:473-512. [PMID: 32149342 PMCID: PMC9137350 DOI: 10.1042/cs20190579] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/17/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022]
Abstract
With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand-receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein-coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.
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Affiliation(s)
- Ryan P Ceddia
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
| | - Sheila Collins
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
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25
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Porter JD, Lindeman SV, Dockendorff C. Modified synthesis of the peptidomimetic natriuretic peptide receptor-C antagonist M372049. Tetrahedron Lett 2020; 61. [DOI: 10.1016/j.tetlet.2020.151654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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26
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Bubb KJ, Aubdool AA, Moyes AJ, Lewis S, Drayton JP, Tang O, Mehta V, Zachary IC, Abraham DJ, Tsui J, Hobbs AJ. Endothelial C-Type Natriuretic Peptide Is a Critical Regulator of Angiogenesis and Vascular Remodeling. Circulation 2019; 139:1612-1628. [PMID: 30586761 DOI: 10.1161/circulationaha.118.036344] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Angiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease and myocardial infarction, which restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. C-type natriuretic peptide (CNP) is a fundamental endothelial signaling species that coordinates vascular homeostasis. Herein, we sought to delineate a central role for CNP in angiogenesis and vascular remodeling in response to ischemia. METHODS The in vitro angiogenic capacity of CNP was examined in pulmonary microvascular endothelial cells and aortic rings isolated from wild-type, endothelium-specific CNP-/-, global natriuretic peptide receptor (NPR)-B-/- and NPR-C-/- animals, and human umbilical vein endothelial cells. These studies were complemented by in vivo investigation of neovascularization and vascular remodeling after ischemia or vessel injury, and CNP/NPR-C expression and localization in tissue from patients with peripheral artery disease. RESULTS Clinical vascular ischemia is associated with reduced levels of CNP and its cognate NPR-C. Moreover, genetic or pharmacological inhibition of CNP and NPR-C, but not NPR-B, reduces the angiogenic potential of pulmonary microvascular endothelial cells, human umbilical vein endothelial cells, and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in endothelium-specific CNP-/- and NPR-C-/-, but not NPR-B-/-, mice; the detrimental phenotype caused by genetic deletion of endothelial CNP, but not NPR-C, can be rescued by pharmacological administration of CNP. The proangiogenic effect of CNP/NPR-C is dependent on activation of Gi, ERK1/2, and phosphoinositide 3-kinase γ/Akt at a molecular level. CONCLUSIONS These data define a central (patho)physiological role for CNP in angiogenesis and vascular remodeling in response to ischemia and provide the rationale for pharmacological activation of NPR-C as an innovative approach to treating peripheral artery disease and ischemic cardiovascular disorders.
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Affiliation(s)
- Kristen J Bubb
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.).,University of Sydney, Kolling Institute of Medical Research, St Leonards, Australia (K.J.B., O.T.)
| | - Aisah A Aubdool
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.)
| | - Amie J Moyes
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.)
| | - Sarah Lewis
- Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Campus, UK (S.L., D.J.A., J.T.)
| | - Jonathan P Drayton
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.)
| | - Owen Tang
- University of Sydney, Kolling Institute of Medical Research, St Leonards, Australia (K.J.B., O.T.)
| | - Vedanta Mehta
- Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, UK (V.M., I.C.Z.)
| | - Ian C Zachary
- Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, UK (V.M., I.C.Z.)
| | - David J Abraham
- Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Campus, UK (S.L., D.J.A., J.T.)
| | - Janice Tsui
- Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Campus, UK (S.L., D.J.A., J.T.)
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK (K.J.B., A.A.A., A.J.M., J.P.D., A.J.H.)
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27
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Domondon M, Nikiforova AB, DeLeon-Pennell KY, Ilatovskaya DV. Regulation of mitochondria function by natriuretic peptides. Am J Physiol Renal Physiol 2019; 317:F1164-F1168. [PMID: 31509010 PMCID: PMC6879937 DOI: 10.1152/ajprenal.00384.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 02/08/2023] Open
Abstract
Natriuretic peptides (NPs) are well known to promote renal Na+ excretion, counteracting the effects of the renin-angiotensin-aldosterone system. Thus, NPs serve as a key component in the maintenance of blood pressure, influencing fluid retention capabilities via osmoregulation. Recently, NPs have been shown to affect lipolysis and enhance lipid oxidation and mitochondrial respiration. Here, we provide an overview of current knowledge about the relationship between NPs and mitochondria-mediated processes such as reactive oxygen species production, Ca2+ signaling, and apoptosis. Establishing a clear physiological and mechanistic connection between NPs and mitochondria in the cardiovascular system will open new avenues of research aimed at understanding and potentially using it as a therapeutic target from a completely new angle.
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Affiliation(s)
- Mark Domondon
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
| | - Anna B Nikiforova
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
| | - Kristine Y DeLeon-Pennell
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
| | - Daria V Ilatovskaya
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina
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28
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Conole D, Myers SH, Mota F, Hobbs AJ, Selwood DL. Biophysical screening methods for extracellular domain peptide receptors, application to natriuretic peptide receptor C ligands. Chem Biol Drug Des 2019; 93:1011-1020. [PMID: 30218492 PMCID: PMC6879014 DOI: 10.1111/cbdd.13395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/15/2018] [Accepted: 09/04/2018] [Indexed: 12/20/2022]
Abstract
Endothelium-derived C-type natriuretic peptide possesses cytoprotective and anti-atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C-type natriuretic peptide are somewhat mediated by the natriuretic peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic peptide receptors. Assay conditions are investigated to explore the feasibility and dynamic range of each method, and peptide-based agonists and antagonists are used as controls to validate these conditions. Once established, each technique was compared and contrasted with respect to their drug discovery utility. We foresee that such techniques will facilitate the discovery and development of potential therapeutic agents for NPR-C and other large extracellular domain membrane receptors.
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Affiliation(s)
- Daniel Conole
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Samuel H. Myers
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Filipa Mota
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Adrian J. Hobbs
- William Harvey Research InstituteHeart Centre, Barts & The London School of MedicineQueen Mary University of LondonLondonUK
| | - David L. Selwood
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
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29
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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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30
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Chen Y, Zheng Y, Iyer SR, Harders GE, Pan S, Chen HH, Ichiki T, Burnett JC, Sangaralingham SJ. C53: A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts. J Mol Cell Cardiol 2019; 130:140-150. [PMID: 30954448 DOI: 10.1016/j.yjmcc.2019.03.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 03/08/2019] [Accepted: 03/31/2019] [Indexed: 01/01/2023]
Abstract
The native particulate guanylyl cyclase B receptor (pGC-B) activator, C-type natriuretic peptide (CNP), induces anti-remodeling actions in the heart and kidney through the generation of the second messenger 3', 5' cyclic guanosine monophosphate (cGMP). Indeed fibrotic remodeling, particularly in cardiorenal disease states, contributes to disease progression and thus, has been a key target for drug discovery and development. Although the pGC-B/cGMP system has been perceived as a promising anti-fibrotic pathway, its therapeutic potential is limited due to the rapid degradation and catabolism of CNP by neprilysin (NEP) and natriuretic peptide clearance receptor (NPRC). The goal of this study was to bioengineer and test in vitro and in vivo a novel pGC-B activator, C53. Here we established that C53 selectively generates cGMP via the pGC-B receptor and is highly resistant to NEP and has less interaction with NPRC in vitro. Furthermore in vivo, C53 had enhanced cGMP-generating actions that paralleled elevated plasma CNP-like levels, thus indicating a longer circulating half-life compared to CNP. Importantly in human cardiac fibroblasts (HCFs) and renal fibroblasts (HRFs), C53 exerted robust cGMP-generating actions, inhibited TGFβ-1 stimulated HCFs and HRFs proliferation chronically and suppressed the differentiation of HCFs and HRFs to myofibroblasts. The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. Future studies are warranted to explore the efficacy and therapeutic opportunity of C53 targeting fibrosis in cardiorenal disease states and beyond.
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Affiliation(s)
- Yang Chen
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States.
| | - Ye Zheng
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - Seethalakshmi R Iyer
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - Gerald E Harders
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - Shuchong Pan
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - Horng H Chen
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - Tomoko Ichiki
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States
| | - John C Burnett
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States; Department of Physiology and Biomedical Engineering, United States
| | - S Jeson Sangaralingham
- Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, United States; Department of Physiology and Biomedical Engineering, United States.
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31
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Kodziszewska K, Sochanowicz B, Brzóska K, Kuśmierczyk M, Kuśmierski K, Śmigielski W, Piotrowski W, Kruszewski M, Leszek P. Natriuretic peptides and their receptors in failing heart - Functional changes and implications for treatment. Int J Cardiol 2018; 265:135-140. [PMID: 29724568 DOI: 10.1016/j.ijcard.2018.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 02/19/2018] [Accepted: 04/05/2018] [Indexed: 11/16/2022]
Affiliation(s)
- Katarzyna Kodziszewska
- Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland.
| | - Barbara Sochanowicz
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland
| | - Kamil Brzóska
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland
| | - Mariusz Kuśmierczyk
- Department of Cardiac Surgery and Transplantology, Institute of Cardiology, Warsaw, Poland
| | - Krzysztof Kuśmierski
- Department of Cardiac Surgery and Transplantology, Institute of Cardiology, Warsaw, Poland
| | - Witold Śmigielski
- Unit of Demography and Social Gerontology at the University of Lodz, Poland; Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion, Institute of Cardiology, Warsaw, Poland
| | - Walerian Piotrowski
- Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion, Institute of Cardiology, Warsaw, Poland
| | - Marcin Kruszewski
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland
| | - Przemyslaw Leszek
- Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland
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32
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Fitzakerley JL, Trachte GJ. Genetics of guanylyl cyclase pathways in the cochlea and their influence on hearing. Physiol Genomics 2018; 50:780-806. [PMID: 29958079 DOI: 10.1152/physiolgenomics.00056.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Although hearing loss is the most common sensory deficit in Western societies, there are no successful pharmacological treatments for this disorder. Recent experiments have demonstrated that manipulation of intracellular cyclic guanosine monophosphate (cGMP) concentrations can have both beneficial and harmful effects on hearing. In this review, we will examine the role of cGMP as a key second messenger involved in many aspects of cochlear function and discuss the known functions of downstream effectors of cGMP in sound processing. The nitric oxide-stimulated soluble guanylyl cyclase system (sGC) and the two natriuretic peptide-stimulated particulate GCs (pGCs) will be more extensively covered because they have been studied most thoroughly. The cochlear GC systems are attractive targets for medical interventions that improve hearing while simultaneously representing an under investigated source of sensorineural hearing loss.
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Affiliation(s)
- Janet L Fitzakerley
- Department of Biomedical Sciences, University of Minnesota Medical School , Duluth, Minnesota
| | - George J Trachte
- Department of Biomedical Sciences, University of Minnesota Medical School , Duluth, Minnesota
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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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MicroRNA-143 modulates the expression of Natriuretic Peptide Receptor 3 in cardiac cells. Sci Rep 2018; 8:7055. [PMID: 29728596 PMCID: PMC5935707 DOI: 10.1038/s41598-018-25489-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 03/01/2018] [Indexed: 12/28/2022] Open
Abstract
Natriuretic Peptide Receptor 3 (NPR3), the clearance receptor for extracellular bio-active natriuretic peptides (NPs), plays important roles in the homeostasis of body fluid volume and vascular tone. Using luciferase reporter and antagomir-based silencing assays, we demonstrated that the expression of NPR3 could be modulated by microRNA-143 (miR-143-3p), a microRNA species with up-regulated circulating concentrations in clinical heart failure. The regulatory effect of miR-143 on NPR3 expression was further evidenced by the reciprocal relationship between miR-143 and NPR3 levels observed in hypoxia-treated human cardiac cells and in left ventricular tissue from rats undergoing experimental myocardial infarction. Further analysis indicated elevation of miR-143 in response to hypoxic challenge reflects transcriptional activation of the miR-143 host gene (MIR143HG). This was corroborated by demonstration of the induction of host gene promoter activity upon hypoxic challenge. Moreover, miR-143 was shown to enhance its own expression by increasing MIR143HG promoter activity, as well as targeting the expressions of NPPA, NPPC, NR3C2, and CRHR2 in cardiac cells. Taken together, these findings suggest that the elevation of miR-143 upon hypoxic insult may be part of a microRNA-based feed forward loop that results in fine tuning the levels of NPs and neurohormonal receptors in cardiac cell lineages.
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Hu Q, Liu Q, Wang S, Zhen X, Zhang Z, Lv R, Jiang G, Ma Z, He H, Li D, Liu X, Gao F, Li J, Li L, Zhang M, Ji X, Chen Y, Wang D, Huang D, Ma A, Huang W, Zhao Y, Gong Y, Zhang C, Zhang Y. NPR-C gene polymorphism is associated with increased susceptibility to coronary artery disease in Chinese Han population: a multicenter study. Oncotarget 2018; 7:33662-74. [PMID: 27191271 PMCID: PMC5085110 DOI: 10.18632/oncotarget.9358] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
To find a new locus that confers significant susceptibility to CAD in Chinese Han population, a genome-wide association study in 200 “extreme individuals” from a Shandong cohort and a pathway-based candidate gene study from a Shanghai cohort (293 CAD/293 controls) were simultaneously performed. Amongst them, 13 SNPs associated with CAD were selected to conduct validation and replication studies in additional 3363 CAD patients and 3148 controls. A novel locus rs700926 in natriuretic peptide receptor C (NPR-C) was identified in Shandong and Hubei cohorts. Then rs700926 and other nine tag SNPs were genotyped in four geographically different populations (Shandong, Shaanxi, Hubei and Sichuan cohorts), and 6 SNPs (rs700926, rs1833529, rs2270915, rs17541471, rs3792758 and rs696831) showed stronger association with CAD, regardless of single or combined analysis. We further genotyped rs2270915 and 10 additional tag SNPs in a central China cohort and identified rs12697273 and rs10066436 as the loci associated with CAD. All these positive associations remained significant after adjustment for traditional risk factors of CAD. NPR-C gene SNPs significantly contribute to CAD susceptibility in the Chinese Han population.
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Affiliation(s)
- Qin Hu
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Qiji Liu
- Department of Medical Genetics, School of Medicine, Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University, Jinan, Shandong, China
| | - Shasha Wang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Xi Zhen
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Zhimian Zhang
- Medical Examination Center, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Ruijuan Lv
- Department of Emergency, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Guihua Jiang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Zhiyong Ma
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Hong He
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Daqing Li
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Xiaoling Liu
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Fei Gao
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Jifu Li
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Li Li
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Mei Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Xiaoping Ji
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Yuguo Chen
- Department of Emergency, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Daowen Wang
- Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Dejia Huang
- Division of Cardiology, Department of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Aiqun Ma
- Department of Cardiology and Periphery Vascular Medicine, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wei Huang
- Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Department of Genetics, Chinese National Human Genome Center, Shanghai, China
| | - Yuxia Zhao
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Yaoqin Gong
- Department of Medical Genetics, School of Medicine, Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University, Jinan, Shandong, China
| | - Cheng Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Yun Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China
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Ren M, Ng FL, Warren HR, Witkowska K, Baron M, Jia Z, Cabrera C, Zhang R, Mifsud B, Munroe PB, Xiao Q, Townsend-Nicholson A, Hobbs AJ, Ye S, Caulfield MJ. The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle. Hum Mol Genet 2018; 27:199-210. [PMID: 29040610 PMCID: PMC5886068 DOI: 10.1093/hmg/ddx375] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 09/28/2017] [Accepted: 09/30/2017] [Indexed: 02/05/2023] Open
Abstract
Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.
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MESH Headings
- Blood Pressure/genetics
- Databases, Nucleic Acid
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/physiology
- Gene Frequency
- Genetic Variation
- Genome-Wide Association Study
- Genotype
- Humans
- Hypertension/genetics
- Hypertension/metabolism
- Hypertension/pathology
- Linkage Disequilibrium
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Polymorphism, Single Nucleotide
- Receptors, Atrial Natriuretic Factor/genetics
- Receptors, Atrial Natriuretic Factor/metabolism
- Signal Transduction
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Affiliation(s)
- Meixia Ren
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
- Fujian Key Laboratory of Geriatrics, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
| | - Fu Liang Ng
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Helen R Warren
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Kate Witkowska
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Michael Baron
- Structural & Molecular Biology, University College London, London, UK
| | - Zhilong Jia
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Core Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China
| | - Claudia Cabrera
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Ruoxin Zhang
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Borbala Mifsud
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Patricia B Munroe
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Qingzhong Xiao
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | | | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
| | - Shu Ye
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
- Shantou University Medical College, Shantou, China
| | - Mark J Caulfield
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Barts Heart Centre, Queen Mary University of London, London, UK
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Verboven K, Hansen D, Jocken JWE, Blaak EE. Natriuretic peptides in the control of lipid metabolism and insulin sensitivity. Obes Rev 2017; 18:1243-1259. [PMID: 28901677 DOI: 10.1111/obr.12598] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/08/2017] [Accepted: 07/20/2017] [Indexed: 12/24/2022]
Abstract
Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in human substrate and energy metabolism, thereby connecting the heart with several insulin-sensitive organs like adipose tissue, skeletal muscle and liver. Obesity may be associated with an impaired regulation of the natriuretic peptide system, also indicated as a natriuretic handicap. Evidence points towards a contribution of this natriuretic handicap to the development of obesity, type 2 diabetes mellitus and cardiometabolic complications, although the causal relationship is not fully understood. Nevertheless, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on current literature regarding the metabolic roles of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Furthermore, it will be discussed how exercise and lifestyle intervention may modulate the natriuretic peptide-related metabolic effects.
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Affiliation(s)
- K Verboven
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.,REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - D Hansen
- REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.,Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
| | - J W E Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - E E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
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A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide. Bioorg Med Chem Lett 2017; 27:3542-3545. [DOI: 10.1016/j.bmcl.2017.05.061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/16/2017] [Accepted: 05/20/2017] [Indexed: 11/23/2022]
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Egom EEA, Feridooni T, Pharithi RB, Khan B, Shiwani HA, Maher V, El Hiani Y, Pasumarthi KBS, Ribama HA. A natriuretic peptides clearance receptor's agonist reduces pulmonary artery pressures and enhances cardiac performance in preclinical models: New hope for patients with pulmonary hypertension due to left ventricular heart failure. Biomed Pharmacother 2017; 93:1144-1150. [PMID: 28738523 DOI: 10.1016/j.biopha.2017.07.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/03/2017] [Accepted: 07/06/2017] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) is common and represents a strong predictor of death. Despite recent advances in the pathophysiological understanding there is as yet no prospect of cure of this deadly clinical entity and the majority of patients continue to progress to right ventricular failure and die. Furthermore, there is no single medical treatment currently approved for PH related to HF. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent the progressive increased or reverse the elevated pulmonary arterial pressures while enhancing cardiac performance in HF. METHOD AND RESULTS We here reported, for the first time, using a pressure-loop (P-V) conductance catheter system, that a specific natriuretic peptides clearance receptors' agonist, the ring-deleted atrial natriuretic peptide analogue, cANF4-23 (cANF) reduces pulmonary artery pressures. Strikingly, the administration of the cANF in these mice decreased the RVSP by 50% (n=5, F 25.687, DF 14, p<0.001) and heart rate (HR) by 11% (n=5, F 25.69, DF 14, p<0.001) as well as enhancing cardiac performance including left ventricular contractility in mice. Most strikingly, mice lacking NPR-C were much more susceptible to develop HF, indicating that NPR-C is a critical protective receptor in the heart. CONCLUSION Natriuretic peptides clearance receptors' agonists may, therefore represent a novel and attractive therapeutic strategy for PH related to HF, and ultimately improves the life expectancy and quality for millions of people around the planet.
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Affiliation(s)
- Emmanuel Eroume-A Egom
- Egom Clinical & Translational Research Services Ltd., Dartmouth, NS B2X 3H3, Canada; Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland.
| | - Tiam Feridooni
- Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
| | - Rebabonye B Pharithi
- Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland
| | - Barkat Khan
- Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland
| | - Haaris A Shiwani
- Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland
| | - Vincent Maher
- Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland
| | - Yassine El Hiani
- Department of Physiology and Biophysics, Dalhousie University, PO Box 15000, Halifax, NS, B3H 4R2, Canada
| | | | - Hilaire A Ribama
- Egom Clinical & Translational Research Services Ltd., Dartmouth, NS B2X 3H3, Canada
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40
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Nakagawa M, Naruko T, Sugioka K, Kitabayashi C, Shirai N, Takagi M, Yoshiyama M, Ohsawa M, Ueda M. Enhanced expression of natriuretic peptide receptor A and B in neutrophils of culprit lesions in patients with acute myocardial infarction. Mol Med Rep 2017; 16:3324-3330. [DOI: 10.3892/mmr.2017.7034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/09/2017] [Indexed: 11/06/2022] Open
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41
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Wong PCY, Guo J, Zhang A. The renal and cardiovascular effects of natriuretic peptides. ADVANCES IN PHYSIOLOGY EDUCATION 2017; 41:179-185. [PMID: 28377431 DOI: 10.1152/advan.00177.2016] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 02/14/2017] [Accepted: 02/27/2017] [Indexed: 06/07/2023]
Abstract
The landmark report by de Bold et al. in 1981 signified the heart as one of the endocrine organs involved in fluid and salt balance (de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. Life Sci 28: 89-94, 1981). Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted from cardiomyocytes in response to cardiac stretch as in the case of heart failure, whereas C-type natriuretic peptide (CNP) is secreted from endothelial and renal cells in response to cytokines and endothelium-dependent agonists, such as acetylcholine. Binding ANP or BNP to natriuretic peptide receptor A induces cyclic guanylyl monophosphate as second messenger in the target cells to mediate the following: natriuresis; water diuresis; increasing glomerular filtration rate; decreasing systemic sympathetic activities; plasma volume; cardiac output and blood pressure; and curbing mitoses of heart fibroblasts and hypertrophy of cardiovascular muscle cells. ANP, BNP, and CNP are cleared from the bloodstream by natriuretic peptide receptor C and degraded by an ectoenzyme called neprilysin (NEP). The plasma levels of BNP are typically >100 pg/ml in patients with congestive heart failure. Sacubitril/valsartan is an angiotensin receptor NEP inhibitor that prevents the clinical progression of surviving patients with heart failure more effectively than enalapril, an angiotensin-converting enzyme inhibitor. A thorough understanding of the renal and cardiovascular effects of natriuretic peptides is of major importance for first-year medical students to gain insight into the significance of plasma levels of BNP in patients with heart failure.
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Affiliation(s)
- Philip Ching Yat Wong
- Department of Cardiology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jun Guo
- Department of Cardiology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Aidong Zhang
- Department of Cardiology, First Affiliated Hospital of Jinan University, Guangzhou, China
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Nagai-Okatani C, Kangawa K, Minamino N. Three molecular forms of atrial natriuretic peptides: quantitative analysis and biological characterization. J Pept Sci 2017; 23:486-495. [PMID: 28120499 DOI: 10.1002/psc.2969] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/22/2016] [Accepted: 12/22/2016] [Indexed: 11/09/2022]
Abstract
Atrial natriuretic peptide (ANP) is primarily produced in the heart tissue and plays a pivotal role in maintaining cardiovascular homeostasis in endocrine and autocrine/paracrine systems and has clinical applications as a biomarker and a therapeutic agent for cardiac diseases. ANP is synthesized by atrial cardiomyocytes as a preprohormone that is processed by a signal peptidase and stored in secretory granules as a prohormone. Subsequent proteolytic processing of ANP by corin during the secretion process results in a bioactive form consisting of 28 amino acid residues. Mechanical stretch of the atrial wall and multiple humoral factors directly stimulates the transcription and secretion of ANP. Secreted ANP elicits natriuretic and diuretic effects via cyclic guanosine monophosphate produced through binding to the guanylyl cyclase-A/natriuretic peptide receptor-A. Circulating ANP is subjected to rapid clearance by a natriuretic peptide receptor-C-mediated mechanism and proteolytic degradation by neutral endopeptidase. In humans, ANP is present as three endogenous molecular forms: bioactive α-ANP, a homodimer of α-ANP designated as β-ANP, and an ANP precursor designated as proANP (also referred to as γ-ANP). The proANP and especially β-ANP, as minor forms in circulation, are notably increased in patients with cardiac diseases, suggesting the utility of monitoring the pathophysiological conditions that result in abnormal proANP processing that cannot be monitored by inactive N-terminal proANP-related fragments. Emerging plate-based sandwich immunoassays for individual quantitation of the three ANP forms enables evaluation of diagnostic implications and net ANP bioactivity. This new tool may provide further understanding in the pathophysiology of cardiac diseases. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
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Affiliation(s)
- Chiaki Nagai-Okatani
- Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Kenji Kangawa
- National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Naoto Minamino
- Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan
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43
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Esapa CT, Piret SE, Nesbit MA, Loh NY, Thomas G, Croucher PI, Brown MA, Brown SDM, Cox RD, Thakker RV. Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway. PLoS One 2016; 11:e0167916. [PMID: 27959934 PMCID: PMC5154531 DOI: 10.1371/journal.pone.0167916] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 11/22/2016] [Indexed: 12/17/2022] Open
Abstract
Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in which loss of plasma membrane NPR3 expression results in increased MAPK pathway activation, causing elongation of the vertebrae and resulting in kyphosis.
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Affiliation(s)
- Christopher T. Esapa
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
- MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Sian E. Piret
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - M. Andrew Nesbit
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Nellie Y. Loh
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Gethin Thomas
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | | | - Matthew A. Brown
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Steve D. M. Brown
- MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Roger D. Cox
- MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Rajesh V. Thakker
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
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44
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Moro C. Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity. Expert Opin Ther Targets 2016; 20:1445-1452. [DOI: 10.1080/14728222.2016.1254198] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Ruiz-Ojeda FJ, Aguilera CM, Rupérez AI, Gil Á, Gomez-Llorente C. An analogue of atrial natriuretic peptide (C-ANP4-23) modulates glucose metabolism in human differentiated adipocytes. Mol Cell Endocrinol 2016; 431:101-8. [PMID: 27181211 DOI: 10.1016/j.mce.2016.05.011] [Citation(s) in RCA: 4] [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: 01/19/2016] [Revised: 04/27/2016] [Accepted: 05/10/2016] [Indexed: 12/21/2022]
Abstract
The present study was undertaken to investigate the effects of C-atrial natriuretic peptide (C-ANP4-23) in human adipose-derived stem cells differentiated into adipocytes over 10 days (1 μM for 4 h). The intracellular cAMP, cGMP and protein kinase A levels were determined by ELISA and gene and protein expression were determined by qRT-PCR and Western blot, respectively, in the presence or absence of C-ANP4-23. The levels of lipolysis and glucose uptake were also determined. C-ANP4-23 treatment significantly increased the intracellular cAMP levels and the gene expression of glucose transporter type 4 (GLUT4) and protein kinase, AMP-activated, alpha 1 catalytic subunit (AMPK). Western blot showed a significant increase in GLUT4 and phosphor-AMPKα levels. Importantly, the adenylate cyclase inhibitor SQ22536 abolished these effects. Additionally, C-ANP4-23 increased glucose uptake by 2-fold. Our results show that C-ANP4-23 enhances glucose metabolism and might contribute to the development of new peptide-based therapies for metabolic diseases.
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Affiliation(s)
- Francisco Javier Ruiz-Ojeda
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain; Instituto de Investigación Biosanitaria ibs, Granada, Spain
| | - Concepción María Aguilera
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain; Instituto de Investigación Biosanitaria ibs, Granada, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain
| | - Azahara Iris Rupérez
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain
| | - Ángel Gil
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain; Instituto de Investigación Biosanitaria ibs, Granada, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain
| | - Carolina Gomez-Llorente
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain; Instituto de Investigación Biosanitaria ibs, Granada, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain.
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46
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Venkatesan B, Tumala A, Subramanian V, Vellaichamy E. Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats. Eur J Pharmacol 2016; 782:44-58. [DOI: 10.1016/j.ejphar.2016.04.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/16/2016] [Accepted: 04/18/2016] [Indexed: 10/21/2022]
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Abstract
cGMP controls many cellular functions ranging from growth, viability, and differentiation to contractility, secretion, and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains. These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular COOH-terminal catalytic (cGMP synthesizing) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptide, stimulating endochondral ossification in autocrine way. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina, and their activation by intracellular Ca(2+)-regulated proteins is essential for vision. Finally, in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO2and by peptidergic (guanylins) and nonpeptidergic odorants as well as by coolness, which has implications for social behaviors. In the past years advances in human and mouse genetics as well as the development of sensitive biosensors monitoring the spatiotemporal dynamics of cGMP in living cells have provided novel relevant information about this receptor family. This increased our understanding of the mechanisms of signal transduction, regulation, and (dys)function of the membrane GCs, clarified their relevance for genetic and acquired diseases and, importantly, has revealed novel targets for therapies. The present review aims to illustrate these different features of membrane GCs and the main open questions in this field.
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Affiliation(s)
- Michaela Kuhn
- Institute of Physiology, University of Würzburg, Würzburg, Germany
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Dewey CM, Spitler KM, Ponce JM, Hall DD, Grueter CE. Cardiac-Secreted Factors as Peripheral Metabolic Regulators and Potential Disease Biomarkers. J Am Heart Assoc 2016; 5:e003101. [PMID: 27247337 PMCID: PMC4937259 DOI: 10.1161/jaha.115.003101] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Colleen M Dewey
- Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Kathryn M Spitler
- Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Jessica M Ponce
- Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Duane D Hall
- Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Chad E Grueter
- Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, Papajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
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49
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The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond) 2016; 130:57-77. [PMID: 26637405 PMCID: PMC5233571 DOI: 10.1042/cs20150469] [Citation(s) in RCA: 209] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
After its discovery in the early 1980s, the natriuretic peptide (NP) system has been extensively characterized and its potential influence in the development and progression of heart failure (HF) has been investigated. HF is a syndrome characterized by the activation of different neurohormonal systems, predominantly the renin-angiotensin (Ang)-aldosterone system (RAAS) and the sympathetic nervous system (SNS), but also the NP system. Pharmacological interventions have been developed to counteract the neuroendocrine dysregulation, through the down modulation of RAAS with ACE (Ang-converting enzyme) inhibitors, ARBs (Ang receptor blockers) and mineralcorticoid antagonists and of SNS with β-blockers. In the last years, growing attention has been paid to the NP system. In the present review, we have summarized the current knowledge on the NP system, focusing on its role in HF and we provide an overview of the pharmacological attempts to modulate NP in HF: from the negative results of the study with neprilysin (NEP) inhibitors, alone or associated with an ACE inhibitor and vasopeptidase inhibitors, to the most recently and extremely encouraging results obtained with the new pharmacological class of Ang receptor and NEP inhibitor, currently defined ARNI (Ang receptor NEP inhibitor). Indeed, this new class of drugs to manage HF, supported by the recent results and a vast clinical development programme, may prompt a conceptual shift in the treatment of HF, moving from the inhibition of RAAS and SNS to a more integrated target to rebalance neurohormonal dysregulation in HF.
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50
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Rossi F, Mascolo A, Mollace V. The pathophysiological role of natriuretic peptide-RAAS cross talk in heart failure. Int J Cardiol 2016; 226:121-125. [PMID: 27062428 DOI: 10.1016/j.ijcard.2016.03.080] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 03/19/2016] [Indexed: 12/22/2022]
Abstract
Chronic Heart Failure (HF) is still a disease state characterized by elevated morbidity and mortality and represents an unresolved problem for its socio-economic impact. Besides many of the pathophysiological events leading to advanced HF have been widely disclosed in the past decades, the role of neuro-hormonal dysregulation accompanying HF has to be clearly assessed with the objective of better therapeutic approaches in treating such a disease. In the present review article, alongside with a brief re-evaluation of general aspects of HF physiopathology, we summarize recent advances in the cross talk between renin-angiotensin-aldosterone system (RAAS) with natriuretic peptides (NPs) which have been shown to play a relevant role in the development of severe HF. The role of RAAS-NPs interplay has been shown to be crucial in both hemodynamic and tissue remodeling associated to cardiomyocyte dysfunction, leading to advanced impairment of left ventricular performance. On the basis of these results, the development of drugs resetting both RAAS and NPs system seems to be promising for a successful long term treatment of chronic HF.
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Affiliation(s)
- Francesco Rossi
- Second University of Naples, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Napoli, Italy
| | - Annamaria Mascolo
- Second University of Naples, Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Napoli, Italy.
| | - Vincenzo Mollace
- Institute of Research for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, Italy
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