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Huang Y, Peng S, Zeng R, Yao H, Feng G, Fang J. From probiotic chassis to modification strategies, control and improvement of genetically engineered probiotics for inflammatory bowel disease. Microbiol Res 2024; 289:127928. [PMID: 39405668 DOI: 10.1016/j.micres.2024.127928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 10/05/2024] [Accepted: 10/05/2024] [Indexed: 11/02/2024]
Abstract
With the rising morbidity of inflammatory bowel disease (IBD) year by year, conventional therapeutic drugs with systemic side effects are no longer able to meet the requirements of patients. Probiotics can improve gut microbiota, enhance intestinal barrier function, and regulate mucosal immunity, making them a potential complementary or alternative therapy for IBD. To compensate for the low potency of probiotics, genetic engineering technology has been widely used to improve their therapeutic function. In this review, we systematically summarize the genetically engineered probiotics used for IBD treatment, including probiotic chassis, genetic modification strategies, methods for controlling probiotics, and means of improving efficacy. Finally, we provide prospects on how genetically engineered probiotics can be extended to clinical applications.
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Affiliation(s)
- Yuewen Huang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China
| | - Shan Peng
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China
| | - Rong Zeng
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China
| | - Hao Yao
- Changsha IMADEK Intelligent Technology Co., LTD, Changsha 410081, China
| | - Guangfu Feng
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
| | - Jun Fang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
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Pleiotropic Roles of Atrial Natriuretic Peptide in Anti-Inflammation and Anti-Cancer Activity. Cancers (Basel) 2022; 14:cancers14163981. [PMID: 36010974 PMCID: PMC9406604 DOI: 10.3390/cancers14163981] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/07/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The relationship between inflammation and carcinogenesis, as well as the response to anti-tumor therapy, is intimate. Atrial natriuretic peptides (ANPs) play a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance. In addition, ANPs exert immune-modulatory effects in the tissue microenvironment, thus exhibiting a fascinating ability to prevent inflammation-related tumorigenesis and cancer recurrence. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs have potential therapeutic value in tumors. Here, we summarized the roles of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs, contributing to the development of ANP-based anti-cancer agents. Abstract The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.
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Chalimeswamy A, Thanuja MY, Ranganath SH, Pandya K, Kompella UB, Srinivas SP. Oxidative Stress Induces a Breakdown of the Cytoskeleton and Tight Junctions of the Corneal Endothelial Cells. J Ocul Pharmacol Ther 2021; 38:74-84. [PMID: 34818079 DOI: 10.1089/jop.2021.0037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose: To investigate the impact of oxidative stress, which is a hallmark of Fuchs dystrophy, on the barrier function of the corneal endothelial cells. Methods: Experiments were carried out with cultured bovine and porcine corneal endothelial cells. For oxidative stress, cells were supplemented with riboflavin (Rf) and exposed to UV-A (15-30 min) to induce Type-1 photochemical reactions that release H2O2. The effect of the stress on the barrier function was assayed by transendothelial electrical resistance (TER) measurement. In addition, the associated changes in the organization of the microtubules, perijunctional actomyosin ring (PAMR), and ZO-1 were evaluated by immunocytochemistry, which was also repeated after direct exposure to H2O2 (100 μM, 1 h). Results: Exposure to H2O2 led to the disassembly of microtubules and the destruction of PAMR. In parallel, the contiguous locus of ZO-1 was disrupted, marking a loss of barrier integrity. Accordingly, a sustained loss in TER was induced when cells in the Rf-supplemented medium were exposed to UV-A. However, the addition of catalase (7,000 U/mL) to rapidly decompose H2O2 limited the loss in TER. Furthermore, the adverse effects on microtubules, PAMR, and ZO-1 were suppressed by including catalase, ascorbic acid (1 mM; 30 min), or pretreatment with p38 MAP kinase inhibitor (SB-203580; 10 μM, 1 h). Conclusions: Acute oxidative stress induces microtubule disassembly by a p38 MAP kinase-dependent mechanism, leading to the destruction of PAMR and loss of barrier function. The response to oxidative stress is reminiscent of the (TNF-α)-induced breakdown of barrier failure in the corneal endothelium.
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Affiliation(s)
- Anupama Chalimeswamy
- Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru, India.,Bio-INvENT Lab, Department of Chemical Engineering, Siddaganga Institute of Technology, Tumakuru, India
| | | | - Sudhir H Ranganath
- Bio-INvENT Lab, Department of Chemical Engineering, Siddaganga Institute of Technology, Tumakuru, India
| | - Kaveet Pandya
- School of Optometry, Indiana University, Bloomington, Indiana, USA
| | - Uday B Kompella
- Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, USA
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Unenkhuu B, Kim DB, Kim HS. MKP-3 suppresses LPS-induced inflammatory responses in HUVECs via inhibition of p38 MAPK/NF-κB pathway. Anim Cells Syst (Seoul) 2021; 25:235-244. [PMID: 34408812 PMCID: PMC8366647 DOI: 10.1080/19768354.2021.1954551] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Endothelial cell dysfunction and inflammatory responses play critical roles in the development of atherosclerosis. Recent data on the processes underlying atherogenesis indicate the substantial role of endotoxins (lipopolysaccharides; LPS) of the intestinal microflora in the initiation and progression of atherosclerosis. Mitogen-activated protein (MAP) kinase phosphatase-3 (MKP-3) is a cytoplasmic dual-specificity protein phosphatase that specifically binds to and inactivates MAP kinases in mammalian cells, but its biological function in endothelial cell dysfunction and inflammatory responses remains largely unknown. The aim of the present study was to investigate the role of MKP-3 in endotoxin-induced endothelial inflammation by western blotting, quantitative polymerase chain reaction, and immunofluorescence. The results of our study demonstrated that MKP-3 overexpression markedly inhibited the adhesion of human monocytic THP-1 cells to human umbilical vein endothelial cells (HUVECs) by downregulating the expression of vascular cell adhesion protein 1 (VCAM-1) and pro-inflammatory cytokines. In contrast, MKP-3-encoding gene knockdown by small interfering RNA (siRNA) exacerbated LPS-induced endothelial dysfunction. Additionally, we found that MKP-3 overexpression inhibited LPS-induced p38 MAPK phosphorylation and decreased the nuclear translocation of nuclear factor kappa B (NF-κB) after LPS treatment, suggesting its implication in the LPS/Toll-like receptor 4 (TLR4)/p38/NF-κB pathway. Overall, these observations suggest that MKP-3 plays a protective role in endothelial dysfunction and may be a therapeutic target.
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Affiliation(s)
- Banzragchgarav Unenkhuu
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Da Bin Kim
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea.,Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea
| | - Hong Seok Kim
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
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Mishra R, Nawas AF, Mendelson CR. Role of NRF2 in immune modulator expression in developing lung. FASEB J 2021; 35:e21758. [PMID: 34245611 DOI: 10.1096/fj.202100129rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 11/11/2022]
Abstract
After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPβ and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPβ, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.
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Affiliation(s)
- Ritu Mishra
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Afshan Fathima Nawas
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Carole R Mendelson
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Obstetrics & Gynecology, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Med Center, Dallas, TX, USA
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Kilian LS, Frank D, Rangrez AY. RhoA Signaling in Immune Cell Response and Cardiac Disease. Cells 2021; 10:1681. [PMID: 34359851 PMCID: PMC8306393 DOI: 10.3390/cells10071681] [Citation(s) in RCA: 2] [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: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/01/2021] [Indexed: 11/25/2022] Open
Abstract
Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.
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Affiliation(s)
- Lucia Sophie Kilian
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Derk Frank
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Ashraf Yusuf Rangrez
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany
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Kilian LS, Voran J, Frank D, Rangrez AY. RhoA: a dubious molecule in cardiac pathophysiology. J Biomed Sci 2021; 28:33. [PMID: 33906663 PMCID: PMC8080415 DOI: 10.1186/s12929-021-00730-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/23/2021] [Indexed: 02/08/2023] Open
Abstract
The Ras homolog gene family member A (RhoA) is the founding member of Rho GTPase superfamily originally studied in cancer cells where it was found to stimulate cell cycle progression and migration. RhoA acts as a master switch control of actin dynamics essential for maintaining cytoarchitecture of a cell. In the last two decades, however, RhoA has been coined and increasingly investigated as an essential molecule involved in signal transduction and regulation of gene transcription thereby affecting physiological functions such as cell division, survival, proliferation and migration. RhoA has been shown to play an important role in cardiac remodeling and cardiomyopathies; underlying mechanisms are however still poorly understood since the results derived from in vitro and in vivo experiments are still inconclusive. Interestingly its role in the development of cardiomyopathies or heart failure remains largely unclear due to anomalies in the current data available that indicate both cardioprotective and deleterious effects. In this review, we aimed to outline the molecular mechanisms of RhoA activation, to give an overview of its regulators, and the probable mechanisms of signal transduction leading to RhoA activation and induction of downstream effector pathways and corresponding cellular responses in cardiac (patho)physiology. Furthermore, we discuss the existing studies assessing the presented results and shedding light on the often-ambiguous data. Overall, we provide an update of the molecular, physiological and pathological functions of RhoA in the heart and its potential in cardiac therapeutics.
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Affiliation(s)
- Lucia Sophie Kilian
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany
| | - Jakob Voran
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany
| | - Derk Frank
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany.
| | - Ashraf Yusuf Rangrez
- Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Rosalind-Franklin Str. 12, 24105, Kiel, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105, Kiel, Germany. .,Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
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Chi Y, Liu X, Chai J. A narrative review of changes in microvascular permeability after burn. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:719. [PMID: 33987417 PMCID: PMC8106041 DOI: 10.21037/atm-21-1267] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Objective We aimed to review and discuss some of the latest research results related to post-burn pathophysiological changes and provide some clues for future study. Background Burns are one of the most common and serious traumas and consist of a series of pathophysiological changes of thermal injury. Accompanied by thermal damage to skin and soft tissues, inflammatory mediators are released in large quantities. Changes in histamine, bradykinin, and cytokines such as vascular endothelial growth factor (VEGF), metabolic factors such as adenosine triphosphate (ATP), and activated neutrophils all affect the body’s vascular permeability. Methods We searched articles with subject words “microvascular permeability”, “burn” “endothelium”, and “endothelial barrier” in PubMed in English published from the beginning of database to Dec, 2020. Conclusions The essence of burn shock is the rapid and extensive fluid transfer in burn and non-burn tissue. After severe burns, the local and systemic vascular permeability increase, causing intravascular fluid extravasation, leading to a progressive decrease in effective circulation volume, an increase in systemic vascular resistance, a decrease in cardiac output, peripheral tissue edema, multiple organ failure, and even death. There are many cells, tissues, mediators and structures involved in the pathophysiological process of the damage to vascular permeability. Ulinastatin is a promising agent for this problem.
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Affiliation(s)
- Yunfei Chi
- Burn Institute, The Fourth Medical Center of the PLA General Hospital, Beijing, China
| | - Xiangyu Liu
- Burn Institute, The Fourth Medical Center of the PLA General Hospital, Beijing, China
| | - Jiake Chai
- Burn Institute, The Fourth Medical Center of the PLA General Hospital, Beijing, China
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Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema? Clin Rev Allergy Immunol 2021; 60:318-347. [PMID: 33725263 PMCID: PMC7962090 DOI: 10.1007/s12016-021-08851-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2021] [Indexed: 02/08/2023]
Abstract
In the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of bradykinin has been studied thoroughly; however, numerous questions remained open regarding the triggering, course, and termination of angioedema attacks. Recently, it became clear that vascular endothelial cells have an integrative role in the regulation of vessel permeability. Apart from bradykinin, a great number of factors of different origin, structure, and mechanism of action are capable of modifying the integrity of vascular endothelium, and thus, may participate in the regulation of angioedema formation. Our aim in this review is to describe the most important permeability factors and the molecular mechanisms how they act on endothelial cells. Based on endothelial cell function, we also attempt to explain some of the challenging findings regarding bradykinin-mediated angioedema, where the function of bradykinin itself cannot account for the pathophysiology. By deciphering the complex scenario of vascular permeability regulation and edema formation, we may gain better scientific tools to be able to predict and treat not only bradykinin-mediated but other types of angioedema as well.
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Chemical composition and antioxidant, cytotoxic, and insecticidal potential of Valeriana alliariifolia in Turkey. Arh Hig Rada Toksikol 2020; 70:207-218. [PMID: 32597129 DOI: 10.2478/aiht-2019-70-3273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 09/01/2019] [Indexed: 12/18/2022] Open
Abstract
Valeriana is a common plant species used for various healing purposes in folk medicine since antiquity. This study investigates the phytochemical profile, antioxidant, cytotoxic, and insecticidal activity of Valeriana alliariifolia Adams, a species that has traditionally been used in Turkey. For the analyses we prepared four root extracts of V. alliariifolia Adams using hexane (HM1), chloroform (CM1), ethanol (EM1), and water (WM1) for maceration. Additionally, two extracts were also prepared from its roots by maceration separately with ethanol (EM2) and water (WM2). One sample was prepared as a water infusion (WI), according to the procedure used in Turkish traditional medicine. The 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation scavenging activity tests showed that ethanol extracts had the strongest antioxidant activity: EM1 (IC50 - DPPH: 17.694 µg/mL; ABTS: 23.8 µg/mL) and EM2 (IC50 - DPPH: 20 µg/mL; ABTS: 21.5 µg/mL). The hexane extract, HM1, was the most cytotoxic (IC50<10 µg/mL against HepG2 and HUVEC) and EM2 strongly cytotoxic (IC50<10 µg/mL against HepG2 and IC50: 11.96 µg/mL against HUVEC). The extracts with demonstrated cytotoxic activities were further examined to check their insecticidal activity against adult female mosquito Aedes aegypti and first instar Ae. aegypti larvae. HM1 was the most effective (90±10 %), which was consistent with its cytotoxic activity. Because of the high antioxidant, cytotoxic, and insecticidal activities, we ran phytochemical analyses of the HM1, EM1, and EM2 extracts with GC-MS (for HM1) and LC-MS/MS (for EM1 and EM2). We also analysed the composition of the essential oil obtained from V. alliariifolia roots by micro-distillation in order to compare its content with HM1, which contains volatile compounds. Phytochemical analyses revealed that the major compound in HM1 was isovaleric acid (16 %) and in the essential oil 1,8-cineole (2.9 %). EM1 and EM2 contained 5-O-caffeoylquinic acid (chlorogenic acid), verbascoside (acteoside), and 3,5-dicaffeoylquinic acid as major components. In the light of our findings and available literature, we can conclude that V. alliariifolia has a good bioactive potential that could be used for different purposes, including the development of new agents for the treatment of various diseases. The difference in the content between the essential oil and HM1 was remarkable. It suggests that the variability observed in the activity of the samples was a result of composition and that, therefore, the aim of treatment should dictate which type of preparation is to be selected. An added value of our study is that it determined verbascoside and methylquercetin rutinoside for the first time in the Valeriana extracts.
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Bellis A, Mauro C, Barbato E, Di Gioia G, Sorriento D, Trimarco B, Morisco C. The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction. Cells 2020; 9:cells9092134. [PMID: 32967374 PMCID: PMC7565478 DOI: 10.3390/cells9092134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/11/2022] Open
Abstract
During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a "multi-targeted cardioprotective therapy", defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.
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Affiliation(s)
- Alessandro Bellis
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica—Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy;
| | - Ciro Mauro
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica—Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy;
| | - Emanuele Barbato
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
| | - Giuseppe Di Gioia
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
- Cardiac Catheterization Laboratory, Montevergine Clinic, 83013 Mercogliano (AV), Italy
| | - Daniela Sorriento
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
| | - Bruno Trimarco
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
| | - Carmine Morisco
- Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; (A.B.); (E.B.); (G.D.G.); (D.S.); (B.T.)
- Correspondence: ; Tel.: +39-081-746-2253; Fax: +39-081-746-2256
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Kennedy K, Keogh B, Lopez C, Adelfio A, Molloy B, Kerr A, Wall AM, Jalowicki G, Holton TA, Khaldi N. An Artificial Intelligence Characterised Functional Ingredient, Derived from Rice, Inhibits TNF-α and Significantly Improves Physical Strength in an Inflammaging Population. Foods 2020; 9:foods9091147. [PMID: 32825524 PMCID: PMC7555431 DOI: 10.3390/foods9091147] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
Food-derived bioactive peptides offer great potential for the treatment and maintenance of various health conditions, including chronic inflammation. Using in vitro testing in human macrophages, a rice derived functional ingredient natural peptide network (NPN) significantly reduced Tumour Necrosis Factor (TNF)-α secretion in response to lipopolysaccharides (LPS). Using artificial intelligence (AI) to characterize rice NPNs lead to the identification of seven potentially active peptides, the presence of which was confirmed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Characterization of this network revealed the constituent peptides displayed anti-inflammatory properties as predicted in vitro. The rice NPN was then tested in an elderly "inflammaging" population with a view to subjectively assess symptoms of digestive discomfort through a questionnaire. While the primary subjective endpoint was not achieved, analysis of objectively measured physiological and physical secondary readouts showed clear significant benefits on the ability to carry out physical challenges such as a chair stand test that correlated with a decrease in blood circulating TNF-α. Importantly, the changes observed were without additional exercise or specific dietary alterations. Further health benefits were reported such as significant improvement in glucose control, a decrease in serum LDL concentration, and an increase in HDL concentration; however, this was compliance dependent. Here we provide in vitro and human efficacy data for a safe immunomodulatory functional ingredient characterized by AI.
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13
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Das S, Neelamegam K, Peters WN, Periyasamy R, Pandey KN. Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21 Cip1 /p27 Kip1 pathways and lead to renal fibrosis and dysfunction. FASEB J 2020; 34:11925-11943. [PMID: 32686172 PMCID: PMC7540536 DOI: 10.1096/fj.202000754r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/08/2020] [Accepted: 06/23/2020] [Indexed: 12/31/2022]
Abstract
Cell-cycle regulatory proteins (p21Cip1 /p27Kip1 ) inhibit cyclin and cyclin-dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1 /p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) gene-knockout (0-copy; Npr1-/- ), 2-copy (Npr1+/+ ), and 4-copy (Npr1++/++ ) mice treated with GC inhibitor, A71915 and cGMP-dependent protein kinase (cGK) inhibitor, (Rp-8-Br-cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0-copy mice and A71915- and Rp-treated 2-copy and 4-copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1 , and p27Kip1 occurred in 0-copy and A71915-treated 2-copy and 4-copy mice, while Rp treatment caused minimal changes than controls. Pro-inflammatory (TNF-α, IL-6) and pro-fibrotic (TGF-β1) cytokines were significantly increased in plasma and kidneys of 0-copy and A71915-treated 2-copy mice, but to lesser extent in 4-copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0-copy and A71915-treated 2-copy and 4-copy mice, but minimally occurred in Rp-treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21Cip1 and p27Kip1 .
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Affiliation(s)
- Subhankar Das
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
| | - Kandasamy Neelamegam
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
| | - Whitney N Peters
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
| | - Ramu Periyasamy
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
| | - Kailash N Pandey
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
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14
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Wang C, Pinar AA, Widdop RE, Hossain MA, Bathgate RAD, Denton KM, Kemp-Harper BK, Samuel CS. The anti-fibrotic actions of relaxin are mediated through AT 2 R-associated protein phosphatases via RXFP1-AT 2 R functional crosstalk in human cardiac myofibroblasts. FASEB J 2020; 34:8217-8233. [PMID: 32297670 DOI: 10.1096/fj.201902506r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 12/19/2022]
Abstract
Fibrosis is a hallmark of several cardiovascular diseases. The relaxin family peptide receptor 1 (RXFP1) agonist, relaxin, has rapidly occurring anti-fibrotic actions which are mediated through RXFP1 and angiotensin II receptor crosstalk on renal and cardiac myofibroblasts. Here, we investigated whether this would allow relaxin to indirectly activate angiotensin II type 2 receptor (AT2 R)-specific signal transduction in primary human cardiac myofibroblasts (HCMFs). The anti-fibrotic effects of recombinant human relaxin (RLX; 16.8 nM) or the AT2 R-agonist, Compound 21 (C21; 1 μM), were evaluated in TGF-β1-stimulated HCMFs, in the absence or presence of an RXFP1 antagonist (1 μM) or AT2 R antagonist (0.1 μM) to confirm RXFP1-AT2 R crosstalk. Competition binding for RXFP1 was determined. Western blotting was performed to determine which AT2 R-specific protein phosphatases were expressed by HCMFs; then, the anti-fibrotic effects of RLX and/or C21 were evaluated in the absence or presence of pharmacological inhibition (NSC95397 (1 μM) for MKP-1; okadaic acid (10 nM) for PP2A) or siRNA-knockdown of these phosphatases after 72 hours. The RLX- or C21-induced increase in ERK1/2 and nNOS phosphorylation, and decrease in α-SMA (myofibroblast differentiation) and collagen-I expression by HCMFs was abrogated by pharmacological blockade of RXFP1 or the AT2 R, confirming RXFP1-AT2 R crosstalk in these cells. HCMFs were found to express AT2 R-dependent MKP-1 and PP2A phosphatases, while pharmacological blockade or siRNA-knockdown of either phosphatase also abolished RLX and/or C21 signal transduction in HCMFs (all P < .05 vs RLX or C21 alone). These findings demonstrated that RLX can indirectly activate AT2 R-dependent phosphatase activity in HCMFs by signaling through RXFP1-AT2 R crosstalk, which have important therapeutic implications for its anti-fibrotic actions.
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Affiliation(s)
- Chao Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Anita A Pinar
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Mohammed A Hossain
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Ross A D Bathgate
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.,Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Kate M Denton
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Physiology, Monash University, Clayton, VIC, Australia
| | - Barbara K Kemp-Harper
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.,Department of Pharmacology, Monash University, Clayton, VIC, Australia.,Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia
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15
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Biagiotti S, Bianchi M, Rossi L, Chessa L, Magnani M. Activation of NRF2 by dexamethasone in ataxia telangiectasia cells involves KEAP1 inhibition but not the inhibition of p38. PLoS One 2019; 14:e0216668. [PMID: 31107893 PMCID: PMC6527213 DOI: 10.1371/journal.pone.0216668] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/26/2019] [Indexed: 01/20/2023] Open
Abstract
Oxidative stress has been shown to play a crucial role in the pathophysiology of the neurodegenerative disease Ataxia Telangiectasia. We have recently demonstrated that Dexamethasone treatment is able to counteract the oxidative state by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation. However, substantial gaps remain in our knowledge of the underlying molecular mechanism(s) according to which Dexamethasone acts as an NRF2 inducer. Herein we investigate the possible effects of the drug on the main NRF2 activation pathways by initially focusing on key kinases known to differently affect NRF2 activation. Neither AKT nor ERK1/2, known to be NRF2-activating kinases, were found to be activated upon Dexamethasone treatment, thus excluding their involvement in the transcription factor nuclear shift. Likewise, GSK3 inactivating kinase was not inhibited, thus ruling out its role in NRF2 activation. On the other hand, p38 MAPK, another NRF2-inhibitory kinase, was indeed switched-off in Ataxia Telangiectasia cells by Dexamethasone-mediated induction of DUSP1 phosphatase, and therefore it appeared that it might account for NRF2 triggering. However, this mechanism was excluded by the use of a selective p38 inhibitor, which failed to cause a significant NRF2 nuclear shift and target gene induction. Finally, dexamethasone effects on the classical oxidative pathway orchestrated by KEAP1 were addressed. Dexamethasone was found to decrease the expression of the inhibitor KEAP1 at both mRNA and protein levels and to induce the shift from the reduced to the oxidized form of KEAP1, thus favouring NRF2 translocation into the nucleus. Furthermore, preliminary data revealed very low levels of the negative regulator Fyn in Ataxia Telangiectasia cells, which might account for the prolonged NRF2-activated gene expression.
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Affiliation(s)
- Sara Biagiotti
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy
- * E-mail:
| | - Marzia Bianchi
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy
| | - Luigia Rossi
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy
| | - Luciana Chessa
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy
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16
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De Angelis E, Pecoraro M, Rusciano MR, Ciccarelli M, Popolo A. Cross-Talk between Neurohormonal Pathways and the Immune System in Heart Failure: A Review of the Literature. Int J Mol Sci 2019; 20:ijms20071698. [PMID: 30959745 PMCID: PMC6480265 DOI: 10.3390/ijms20071698] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/01/2019] [Accepted: 04/02/2019] [Indexed: 02/06/2023] Open
Abstract
Heart failure is a complex clinical syndrome involving a multitude of neurohormonal pathways including the renin-angiotensin-aldosterone system, sympathetic nervous system, and natriuretic peptides system. It is now emerging that neurohumoral mechanisms activated during heart failure, with both preserved and reduced ejection fraction, modulate cells of the immune system. Indeed, these cells express angiotensin I receptors, adrenoceptors, and natriuretic peptides receptors. Ang II modulates macrophage polarization, promoting M2 macrophages phenotype, and this stimulation can influence lymphocytes Th1/Th2 balance. β-AR activation in monocytes is responsible for inhibition of free oxygen radicals production, and together with α2-AR can modulate TNF-α receptor expression and TNF-α release. In dendritic cells, activation of β2-AR inhibits IL-12 production, resulting in the inhibition of Th1 and promotion of Th2 differentiation. ANP induces the activation of secretion of superoxide anion in polymorphonucleated cells; reduces TNF-α and nitric oxide secretion in macrophages; and attenuates the exacerbated TH1 responses. BNP in macrophages can stimulate ROS production, up-regulates IL-10, and inhibits IL-12 and TNF-α release by dendritic cells, suggesting an anti-inflammatory cytokines profile induction. Therefore, different neurohormonal-immune cross-talks can determine the phenotype of cardiac remodeling, promoting either favorable or maladaptive responses. This review aims to summarize the available knowledge on neurohormonal modulation of immune responses, providing supportive rational background for further research.
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Affiliation(s)
- Elena De Angelis
- Department of Medicine, Surgery and Odontology, University of Salerno, via S.Allende 1, 84081 Baronissi (SA), Italy.
| | - Michela Pecoraro
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Odontology, University of Salerno, via S.Allende 1, 84081 Baronissi (SA), Italy.
- Casa di Cura Montevergine, 83013 Mercogliano (AV), Italy.
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Odontology, University of Salerno, via S.Allende 1, 84081 Baronissi (SA), Italy.
| | - Ada Popolo
- Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
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17
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Periyasamy R, Das S, Pandey KN. Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates renal (pro) renin receptor expression in Npr1 null mutant mice. Peptides 2019; 114:17-28. [PMID: 30965084 PMCID: PMC6821518 DOI: 10.1016/j.peptides.2019.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 03/08/2019] [Accepted: 03/11/2019] [Indexed: 01/01/2023]
Abstract
The objective of the present study was to determine whether targeted-disruption of Npr1 gene (encoding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to the activation of MAPKs in Npr1 gene-knockout mice. The Npr1 homozygous (Npr1-/-; 0-copy), heterozygous (Npr1+/-; 1-copy), wild-type (Npr1+/+; 2-copy), and gene-duplicated (Npr1++/++; 4-copy) mice were utilized. To identify the canonical pathway of (P)RR, we administered ACE-1 inhibitor (captopril), AT1R blocker (losartan), and MAPKs inhibitors (U0126 and SB203580) to all Npr1 mice genotypes. The renal expression of (P)RR mRNA was increased by 3-fold in 0-copy mice and 2-fold in 1-copy mice compared with 2-copy mice, which was also associated with significantly increased expression of ACE-1 and AT1R mRNA levels. Similarly, the phosphorylation of MAPKs (Erk1/2 and p-p38) was enhanced by 3.5-fold and 3.2-fold, respectively, in 0-copy mice with significant increases in 1-copy mice compared with 2-copy mice. The kidney and plasma levels of proinflammatory cytokines were significantly elevated in 0-copy and 1-copy mice. Treatment with captopril and losartan did not alter the expression of (P)RR in any of the Npr1 mice genotypes. Interestingly, losartan significantly reduced the phosphorylation of Erk1/2 and p38 in Npr1 mice. The present results suggest that the ablation of Npr1 upregulates (P)RR, MAPKs (Erk1/2 and p38), and proinflammatory cytokines in 0-copy and 1-copy mice. In contrast, the duplication of Npr1 exhibits the anti-inflammatory and antihypertensive effects by reducing the activation of MAPKs and inhibiting the expression levels of RAAS components and proinflammatory cytokines.
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Affiliation(s)
- Ramu Periyasamy
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, United States
| | - Subhankar Das
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, United States
| | - Kailash N Pandey
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, United States.
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18
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Neutrophil-Initiated Myocardial Inflammation and Its Modulation by B-Type Natriuretic Peptide: A Potential Therapeutic Target. Int J Mol Sci 2018; 20:ijms20010129. [PMID: 30602672 PMCID: PMC6337677 DOI: 10.3390/ijms20010129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/19/2018] [Accepted: 12/22/2018] [Indexed: 12/11/2022] Open
Abstract
Activation of neutrophils is a critically important component of the innate immune response to bacterial and chemical stimuli, and culminates in the “neutrophil burst”, which facilitates neutrophil phagocytosis via the release of superoxide anion radical (O2−) from NADPH oxidase. Excessive and/or prolonged neutrophil activation results in substantial tissue injury and increases in vascular permeability—resulting in sustained tissue infiltration with neutrophils and monocytes, and persistent vasomotor dysfunction. Cardiovascular examples of such changes include acute and chronic systolic and diastolic heart failure (“heart failure with preserved ejection fraction”), and the catecholamine-induced inflammatory disorder takotsubo syndrome. We have recently demonstrated that B-type natriuretic peptide (BNP), acting via inhibition of activation of neutrophil NADPH oxidase, is an important negative modulator of the “neutrophil burst”, though its effectiveness in limiting tissue injury is partially lost in acute heart failure. The potential therapeutic implications of these findings, regarding the development of new means of treating both acute and chronic cardiac injury states, are discussed.
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19
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Zhang Y, Ma KL, Gong YX, Wang GH, Hu ZB, Liu L, Lu J, Chen PP, Lu CC, Ruan XZ, Liu BC. Platelet Microparticles Mediate Glomerular Endothelial Injury in Early Diabetic Nephropathy. J Am Soc Nephrol 2018; 29:2671-2695. [PMID: 30341150 DOI: 10.1681/asn.2018040368] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 09/18/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.
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Affiliation(s)
- Yang Zhang
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Kun Ling Ma
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Yu Xiang Gong
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Gui Hua Wang
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Ze Bo Hu
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Liang Liu
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Jian Lu
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Pei Pei Chen
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Chen Chen Lu
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
| | - Xiong Zhong Ruan
- Centre for Nephrology, University College London Medical School, London, UK
| | - Bi Cheng Liu
- Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and
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20
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He X, Zeng H, Roman RJ, Chen JX. Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre-existing diastolic dysfunction in mice. Int J Cardiol 2018; 272:281-287. [PMID: 30177233 DOI: 10.1016/j.ijcard.2018.08.065] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/09/2018] [Accepted: 08/22/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Diastolic dysfunction is emerging as a leading cause of heart failure in aging population. Induction of hypoxia tolerance and reprogrammed cell metabolism have emerged as novel therapeutic strategies for the treatment of cardiovascular diseases. METHODS AND RESULTS In the present study, we showed that deletion of sirtuin 3 (SIRT3) resulted in a diastolic dysfunction together with a significant increase in the expression of prolyl hydroxylases (PHD) 1 and 2. We further investigated the involvement of PHD in the development of diastolic dysfunction by treating the 12-14 months old mice with a PHD inhibitor, dimethyloxalylglycine (DMOG) for 2 weeks. DMOG treatment increased the expression of hypoxia-inducible factor (HIF)-1α in the endothelium of coronary arteries. This was accompanied by a significant improvement of coronary flow reserve and diastolic function. Inhibition of PHD altered endothelial metabolism by increasing glycolysis and reducing oxygen consumption. Most importantly, treatment with DMOG completely reversed the pre-existing diastolic dysfunction in the endothelial-specific SIRT3 deficient mice. CONCLUSIONS Our findings demonstrate that inhibition of PHD and reprogrammed cell metabolism can reverse the pre-existed diastolic dysfunction in SIRT3 deficient mice. Our study provides a potential therapeutic strategy of induction of hypoxia tolerance for patients with diastolic dysfunction associated with coronary microvascular dysfunction, especially in the aging population with reduced SIRT3.
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Affiliation(s)
- Xiaochen He
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Heng Zeng
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Richard J Roman
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Jian-Xiong Chen
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
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21
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Affiliation(s)
- Yao Xie
- From the Cardiovascular Division, King's College London BHF Centre, London, UK (Y.X., Q.X.); and Institute of Respiratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.F.)
| | - Ye Fan
- From the Cardiovascular Division, King's College London BHF Centre, London, UK (Y.X., Q.X.); and Institute of Respiratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.F.)
| | - Qingbo Xu
- From the Cardiovascular Division, King's College London BHF Centre, London, UK (Y.X., Q.X.); and Institute of Respiratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.F.).
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22
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Hsu SF, Lee YB, Lee YC, Chung AL, Apaya MK, Shyur LF, Cheng CF, Ho FM, Meng TC. Dual specificity phosphatase DUSP6 promotes endothelial inflammation through inducible expression of ICAM-1. FEBS J 2018; 285:1593-1610. [PMID: 29493888 DOI: 10.1111/febs.14425] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 02/12/2018] [Accepted: 02/23/2018] [Indexed: 12/30/2022]
Abstract
Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases.
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Affiliation(s)
- Shu-Fang Hsu
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Yu-Bin Lee
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Ying-Chu Lee
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Ai-Ling Chung
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | | | - Lie-Fen Shyur
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Ching-Feng Cheng
- Department of Medical Research, Tzu Chi University, Hualien, Taiwan.,Department of Pediatrics, Tzu Chi General Hospital, Hualien, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Feng-Ming Ho
- Department of Internal Medicine, Taipei Medical University, Taiwan.,Division of Cardiology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan.,R&D Center for Membrane Technology, Department of Chemical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan
| | - Tzu-Ching Meng
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
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23
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Li X, Liang Y, Qiao Z, Yang J, Han P, Zhao B, Li F, Lv H, Guo J, Gao F, Li L. Transcriptional Analysis of Endothelial Cell Alternation Induced by Atrial Natriuretic Polypeptide in Human Umbilical Vein Endothelial Cells. Int Heart J 2018; 59:197-202. [PMID: 29279524 DOI: 10.1536/ihj.16-522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The aim of this study was to explore how atrial natriuretic polypeptide (ANP) affects the properties and function of endothelial cells. Gene expression data GSE56976 generated at 0, 1, and 6 hours after ANP incubation in human umbilical vein endothelial cells (HUVEC) was used. Microarray data were preprocessed for differentially expressed genes (DEGs) in each time-dependent group. Next, gene ontology (GO), pathway analysis, and transcriptional regulation were performed. Co-expression clustering analysis of DEGs and functional enrichment analysis of co-expression modules were processed. RT-PCR analysis was performed to validate gene expression. DEGs were obtained and their counts were increased from 0 hours to 6 hours. No overlapping DEGs were obtained among the 3 groups. The DEGs of ANP_6hours, including TGFB2 (transforming growth factor, beta 2), LTF (lactotransferrin/lactoferrin), and ETV7 (Ets variant 7) were mainly related with cell apoptosis and immune responses. The DEGs in the network of ANP_0hour were mainly associated with epithelial ion transport processes. In addition, 3 co-expressed modules were detected. CSF2 (colony stimulating factor 2) and PF4 (platelet factor 4) of the blue module were related with cytolysis, while FXYD1 (FXYD domain containing ion transport regulator 1) and TGFB2 of the yellow module were mainly enriched in ion transport and the ovulation cycle. The expression of TGFB2 obtained by microarray analysis was consistent with that of RT-PCR. Ion transport could be affected promptly after ANP treatment, and subsequently, the cytolysis of vein endothelial cells may be promoted and endothelial permeability would be enhanced, followed by activated immune responses.
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Affiliation(s)
- Xuefeng Li
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Yu Liang
- Nursing College of Mudanjiang Medical College
| | - Zhili Qiao
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Jiaoxia Yang
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | | | | | - Fengxiang Li
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Hengjuan Lv
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Jifang Guo
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Fengmin Gao
- Department of Cardiology, Hongqi Hospital, Mudanjiang Medical College
| | - Li Li
- Department of Physiology, Mudanjiang Medical College
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24
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Frantz S, Falcao-Pires I, Balligand JL, Bauersachs J, Brutsaert D, Ciccarelli M, Dawson D, de Windt LJ, Giacca M, Hamdani N, Hilfiker-Kleiner D, Hirsch E, Leite-Moreira A, Mayr M, Thum T, Tocchetti CG, van der Velden J, Varricchi G, Heymans S. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC. Eur J Heart Fail 2018; 20:445-459. [PMID: 29333691 PMCID: PMC5993315 DOI: 10.1002/ejhf.1138] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 12/03/2017] [Accepted: 12/18/2017] [Indexed: 12/11/2022] Open
Abstract
Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.
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Affiliation(s)
- Stefan Frantz
- Department of Internal Medicine I, University Hospital Würzburg, Germany; Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ines Falcao-Pires
- Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Jean-Luc Balligand
- Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC), and Clinique Universitaire Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Medizinische Hochschule, Hannover, Germany
| | | | - Michele Ciccarelli
- Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Dana Dawson
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland
| | - Leon J de Windt
- Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Mauro Giacca
- International Centre for Genetic Engineering and Biotechnology (ICGEB) and Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Nazha Hamdani
- Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany
| | - Denise Hilfiker-Kleiner
- Molecular Cardiology, Department of Cardiology and Angiology, Medizinische Hochschule, Hannover, Germany
| | - Emilio Hirsch
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Adelino Leite-Moreira
- Department of Physiology and Cardiothoracic Surgery and Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Manuel Mayr
- The James Black Centre and King's British Heart Foundation Centre, King's College, University of London, London, UK
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx, and REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany
| | - Carlo G Tocchetti
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Jolanda van der Velden
- Department of Physiology, VU University Medical Center, Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands.,Netherlands Heart Institute, Utrecht, The Netherlands
| | - Gilda Varricchi
- Department of Translational Medical Sciences, Federico II University, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy
| | - Stephane Heymans
- Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.,Netherlands Heart Institute, Utrecht, The Netherlands.,Department of Cardiovascular Sciences, Leuven University, Leuven, Belgium
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25
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Cheng HH, Chu LY, Chiang LY, Chen HL, Kuo CC, Wu KK. Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan. Oncotarget 2017; 7:31243-56. [PMID: 27145282 PMCID: PMC5058753 DOI: 10.18632/oncotarget.9111] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 04/11/2016] [Indexed: 11/25/2022] Open
Abstract
We reported previously that human fibroblasts release 5-methoxytryptophan (5-MTP) which inhibits cancer cell COX-2 overexpression and suppresses cancer cell migration and metastasis. To determine whether fibroblasts block cancer cell epithelial mesenchymal transition (EMT) via 5-MTP, we evaluated the effect of Hs68 fibroblasts (HsFb) on A549 cancer cell EMT in a two-chamber system. Co-incubation of A549 with HsFb prevented TGF-β1-induced reduction of E-cadherin and increase in Snail and N-cadherin. Transfection of HsFb with tryptophan hydroxylase-1 siRNA, which inhibited tryptophan hydroxylase-1 protein expression and 5-MTP release in HsFb abrogated the effect of HsFb on A549 EMT. Direct addition of pure 5-MTP to cultured A549 cells followed by TGF-β1 prevented TGF-β1-induced reduction of E-cadherin, and elevation of Snail, vimentin and matrix metalloproteinase 9. Administration of 5-MTP to a murine xenograft tumor model reduced vimentin protein expression in the tumor tissues compared to vehicle control which was correlated with reduction of metastasis in the 5-MTP treated mice. Our experimental data suggest that 5-MTP exerted its anti-EMT actions through inhibition of p38 MAPK activation, p65/p50 NF-κB nuclear translocation and transactivation without the involvement of COX-2 or p300 histone acetyltransferase. Our findings indicate that fibroblasts release a tryptophan metabolite, 5-MTP, to reduce cancer cell EMT, migration, invasion and metastasis.
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Affiliation(s)
- Huei-Hsuan Cheng
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Ling-Yun Chu
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Li-Yi Chiang
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Hua-Ling Chen
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Cheng-Chin Kuo
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.,Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Kenneth K Wu
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.,Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.,Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan
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26
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Meyer P, Maity P, Burkovski A, Schwab J, Müssel C, Singh K, Ferreira FF, Krug L, Maier HJ, Wlaschek M, Wirth T, Kestler HA, Scharffetter-Kochanek K. A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence. PLoS Comput Biol 2017; 13:e1005741. [PMID: 29206223 PMCID: PMC5730191 DOI: 10.1371/journal.pcbi.1005741] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 12/14/2017] [Accepted: 08/22/2017] [Indexed: 12/21/2022] Open
Abstract
Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.
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Affiliation(s)
- Patrick Meyer
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
| | - Pallab Maity
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
| | - Andre Burkovski
- Institute of Medical Systems Biology, University of Ulm, Germany
- International Graduate School in Molecular Medicine, University of Ulm, Germany
| | - Julian Schwab
- Institute of Medical Systems Biology, University of Ulm, Germany
- International Graduate School in Molecular Medicine, University of Ulm, Germany
| | - Christoph Müssel
- Institute of Medical Systems Biology, University of Ulm, Germany
| | - Karmveer Singh
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
| | - Filipa F. Ferreira
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
| | - Linda Krug
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
| | | | - Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
| | - Thomas Wirth
- Institute of Physiological Chemistry, University of Ulm, Germany
| | - Hans A. Kestler
- Aging Research Center (ARC), University of Ulm, Germany
- Institute of Medical Systems Biology, University of Ulm, Germany
| | - Karin Scharffetter-Kochanek
- Department of Dermatology and Allergic Diseases, University of Ulm, Germany
- Aging Research Center (ARC), University of Ulm, Germany
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27
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M 3 receptor is involved in the effect of penehyclidine hydrochloride reduced endothelial injury in LPS-stimulated human pulmonary microvascular endothelial cell. Pulm Pharmacol Ther 2017; 48:144-150. [PMID: 29158153 DOI: 10.1016/j.pupt.2017.11.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 09/19/2017] [Accepted: 11/17/2017] [Indexed: 11/20/2022]
Abstract
LPS has been recently shown to induce muscarinic acetylcholine 3 receptor (M3 receptor) expression and penehyclidine hydrochloride (PHC) is an anticholinergic drug which could block the expression of M3 receptor. PHC has been demonstrated to perform protective effect on cell injury. This study is to investigate whether the effect of PHC on microvascular endothelial injury is related to its inhibition of M3 receptor or not. HPMVECs were treated with specific M3 receptor shRNA or PBS, and randomly divided into LPS group (A group), LPS+PHC group (B group), LPS + M3 shRNA group (C group) and LPS + PHC + M3 shRNA group (D group). Cells were collected at 60 min after LPS treatment to measure levels of LDH, endothelial permeability, TNF-α and IL-6 levels, NF-κB p65 activation, I-κB protein expression, p38MAPK, and ERK1/2 activations as well as M3 mRNA expression. PHC could decrease LDH levels, cell permeability, TNF-α and IL-6 levels, p38 MAPK, ERK1/2, NF-κB p65 activations and M3 mRNA expressions compared with LPS group. When M3 receptor was silence, the changes of these indices were much more obvious. These findings suggest that M3 receptor plays an important role in LPS-induced pulmonary microvascular endothelial injury, which is regulated through NF-κB p65 and MAPK activation. And knockout of M3 receptor could attenuate LPS-induced pulmonary microvascular endothelial injury. Regulative effects of PHC on pulmonary microvascular permeability and NF-κB p65 as well as MAPK activations are including but not limited to inhibition of M3 receptor.
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28
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Santhekadur PK, Kumar DP, Seneshaw M, Mirshahi F, Sanyal AJ. The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed Pharmacother 2017; 92:826-835. [PMID: 28599248 PMCID: PMC5737745 DOI: 10.1016/j.biopha.2017.05.136] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/25/2017] [Accepted: 05/28/2017] [Indexed: 12/19/2022] Open
Abstract
Due to globalization and sophisticated western and sedentary lifestyle, metabolic syndrome has emerged as a serious public health challenge. Obesity is significantly increasing worldwide because of increased high calorie food intake and decreased physical activity leading to hypertension, dyslipidemia, atherosclerosis, and insulin resistance. Thus, metabolic syndrome constitutes cardiovascular disease, type 2 diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD) and recently some cancers are also considered to be associated with this syndrome. There is increasing evidence of the involvement of natriuretic peptides (NP) in the pathophysiology of metabolic diseases. The natriuretic peptides are cardiac hormones, which are produced in the cardiac atrium, ventricles of the heart and the endothelium. These peptides are involved in the homeostatic control of body water, sodium intake, potassium transport, lipolysis in adipocytes and regulates blood pressure. The three known natriuretic peptide hormones present in the natriuretic system are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and c-type natriuretic peptide (CNP). These three peptides primarily function as endogenous ligands and mainly act via their membrane receptors such as natriuretic peptide receptor A (NPR-A), natriuretic peptide receptor B (NPR-B) and natriuretic peptide receptor C (NPR-C) and regulate various physiological and metabolic functions. This review will shed light on the structure and function of natriuretic peptides and their receptors and their role in the metabolic syndrome.
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Affiliation(s)
- Prasanna K Santhekadur
- McGuire Research Institute, McGuire Veterans Affairs Medical Center, Richmond, VA, USA; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
| | - Divya P Kumar
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Mulugeta Seneshaw
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Faridoddin Mirshahi
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Arun J Sanyal
- McGuire Research Institute, McGuire Veterans Affairs Medical Center, Richmond, VA, USA; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
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29
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Kim HS, Asmis R. Mitogen-activated protein kinase phosphatase 1 (MKP-1) in macrophage biology and cardiovascular disease. A redox-regulated master controller of monocyte function and macrophage phenotype. Free Radic Biol Med 2017; 109:75-83. [PMID: 28330703 PMCID: PMC5462841 DOI: 10.1016/j.freeradbiomed.2017.03.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/03/2017] [Accepted: 03/17/2017] [Indexed: 12/21/2022]
Abstract
MAPK pathways play a critical role in the activation of monocytes and macrophages by pathogens, signaling molecules and environmental cues and in the regulation of macrophage function and plasticity. MAPK phosphatase 1 (MKP-1) has emerged as the main counter-regulator of MAPK signaling in monocytes and macrophages. Loss of MKP-1 in monocytes and macrophages in response to metabolic stress leads to dysregulation of monocyte adhesion and migration, and gives rise to dysfunctional, proatherogenic monocyte-derived macrophages. Here we review the properties of this redox-regulated dual-specificity MAPK phosphatase and the role of MKP-1 in monocyte and macrophage biology and cardiovascular diseases.
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Affiliation(s)
- Hong Seok Kim
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea; Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea
| | - Reto Asmis
- Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
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30
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Oskolkova O, Gawlak G, Tian Y, Ke Y, Sarich N, Son S, Andreasson K, Bochkov VN, Birukova AA, Birukov KG. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. FASEB J 2017; 31:4187-4202. [PMID: 28572443 DOI: 10.1096/fj.201601232rr] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 05/08/2017] [Indexed: 01/08/2023]
Abstract
Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) oxidation that contain cyclopenthenone groups, which recapitulate prostaglandin-like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by oxidized PAPC (OxPAPC) remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-α. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti-inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.
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Affiliation(s)
- Olga Oskolkova
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Grzegorz Gawlak
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Yufeng Tian
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Yunbo Ke
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Nicolene Sarich
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Sophia Son
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Katrin Andreasson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
| | - Valery N Bochkov
- Department of Pharmaceutical Chemistry, University of Graz, Graz, Austria
| | - Anna A Birukova
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Konstantin G Birukov
- Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA;
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31
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Podewin T, Broichhagen J, Frost C, Groneberg D, Ast J, Meyer-Berg H, Fine NHF, Friebe A, Zacharias M, Hodson DJ, Trauner D, Hoffmann-Röder A. Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. Chem Sci 2017; 8:4644-4653. [PMID: 28626572 PMCID: PMC5471452 DOI: 10.1039/c6sc05044a] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/09/2017] [Indexed: 12/11/2022] Open
Abstract
The optical control over biological function with small photoswitchable molecules has gathered significant attention in the last decade. Herein, we describe the design and synthesis of a small library of photoswitchable peptidomimetics based upon human atrial natriuretic peptide (ANP), in which the photochromic amino acid [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is incorporated into the peptide backbone. The endogeneous hormone ANP signals via the natriuretic peptide receptor A (NPR-A) through raising intracellular cGMP concentrations, and is involved in blood pressure regulation and sodium homeostasis, as well as lipid metabolism and pancreatic function. The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro. Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch. Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans. This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.
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Affiliation(s)
- Tom Podewin
- Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . ;
| | - Johannes Broichhagen
- Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . ;
| | - Christina Frost
- Department of Physics , Technical University of Munich , James-Franck-Str. 1 , 85748 Garching , Germany
| | - Dieter Groneberg
- Julius-Maximilian-University Würzburg , Institute of Physiology , Röntgenring 9 , 97070 Würzburg , Germany
| | - Julia Ast
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE) , University of Birmingham , Edgbaston , B15 2TT , UK
- Centre for Endocrinology , Diabetes and Metabolism , Birmingham Health Partners , Birmingham , B15 2TH , UK
| | - Helena Meyer-Berg
- Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . ;
| | - Nicholas H F Fine
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE) , University of Birmingham , Edgbaston , B15 2TT , UK
- Centre for Endocrinology , Diabetes and Metabolism , Birmingham Health Partners , Birmingham , B15 2TH , UK
| | - Andreas Friebe
- Julius-Maximilian-University Würzburg , Institute of Physiology , Röntgenring 9 , 97070 Würzburg , Germany
| | - Martin Zacharias
- Department of Physics , Technical University of Munich , James-Franck-Str. 1 , 85748 Garching , Germany
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE) , University of Birmingham , Edgbaston , B15 2TT , UK
- Centre for Endocrinology , Diabetes and Metabolism , Birmingham Health Partners , Birmingham , B15 2TH , UK
| | - Dirk Trauner
- Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . ;
| | - Anja Hoffmann-Röder
- Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . ;
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Zhang Y, Li X, Liu LP, Hong L, Liu X, Zhang B, Wu CZ, Cui X. Peroxisome proliferator-activated receptor γ is essential for secretion of ANP induced by prostaglandin D 2 in the beating rat atrium. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2017; 21:293-300. [PMID: 28461771 PMCID: PMC5409115 DOI: 10.4196/kjpp.2017.21.3.293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/09/2016] [Accepted: 12/12/2016] [Indexed: 12/14/2022]
Abstract
Prostaglandin D2 (PGD2) may act against myocardial ischemia-reperfusion (I/R) injury and play an anti-inflammatory role in the heart. Although the effect of PGD2 in regulation of ANP secretion of the atrium was reported, the mechanisms involved are not clearly identified. The aim of the present study was to investigate whether PGD2 can regulate ANP secretion in the isolated perfused beating rat atrium, and its underlying mechanisms. PGD2 (0.1 to 10 µM) significantly increased atrial ANP secretion concomitantly with positive inotropy in a dose-dependent manner. Effects of PGD2 on atrial ANP secretion and mechanical dynamics were abolished by AH-6809 (1.0 µM) and AL-8810 (1.0 µM), PGD2 and prostaglandin F2α (PGF2α) receptor antagonists, respectively. Moreover, PGD2 clearly upregulated atrial peroxisome proliferator-activated receptor gamma (PPARγ) and the PGD2 metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, 0.1 µM) dramatically increased atrial ANP secretion. Increased ANP secretions induced by PGD2 and 15d-PGJ2 were completely blocked by the PPARγ antagonist GW9662 (0.1 µM). PD98059 (10.0 µM) and LY294002 (1.0 µM), antagonists of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling, respectively, significantly attenuated the increase of atrial ANP secretion by PGD2. These results indicated that PGD2 stimulated atrial ANP secretion and promoted positive inotropy by activating PPARγ in beating rat atria. MAPK/ERK and PI3K/Akt signaling pathways were each partially involved in regulating PGD2-induced atrial ANP secretion.
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Affiliation(s)
- Ying Zhang
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China.,Institue of Clinical Medicine, Yanbian University, Yanji 133-002, China
| | - Xiang Li
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China
| | - Li-Ping Liu
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China
| | - Lan Hong
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China
| | - Xia Liu
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China
| | - Bo Zhang
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China
| | - Cheng-Zhe Wu
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China.,Institue of Clinical Medicine, Yanbian University, Yanji 133-002, China
| | - Xun Cui
- Department of Physiology, School of Medicine, Yanbian University, Yanji 133-002, China.,Key Laboratory of Organism Functional Factors of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133-002, China.,Cellular Function Research Center, Yanbian University, Yanji 133-002, China
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Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. Sci Rep 2017; 7:46624. [PMID: 28429785 PMCID: PMC5399490 DOI: 10.1038/srep46624] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/22/2017] [Indexed: 12/11/2022] Open
Abstract
Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.
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Mitaka C, Ohnuma T, Murayama T, Kunimoto F, Nagashima M, Takei T, Iguchi N, Tomita M. Effects of low-dose atrial natriuretic peptide infusion on cardiac surgery-associated acute kidney injury: A multicenter randomized controlled trial. J Crit Care 2016; 38:253-258. [PMID: 27997877 DOI: 10.1016/j.jcrc.2016.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 12/01/2016] [Accepted: 12/07/2016] [Indexed: 11/17/2022]
Abstract
PURPOSE To evaluate the effects of atrial natriuretic peptide (ANP) on renal function and medical costs in patients with acute kidney injury (AKI) associated with cardiac surgery. MATERIALS AND METHODS The Japanese trial for AKI in Post-cardiovascular surgery patients by ANP (JAPAN) was a prospective, multicenter, randomized, double-blind, placebo-controlled study conducted in 11 hospitals in Japan. Acute kidney injury was defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours. The patients were randomly assigned to receive ANP (0.02 μg kg-1 min-1) or placebo. The primary end point was a change in renal function. The secondary end points were a need for renal replacement therapy, the lengths of intensive care unit and hospital stays, and medical costs incurred over the 90-day follow-up. RESULTS Of the 77 randomized patients, 37 were in the ANP group and 40 were in the placebo group. Although ANP significantly (P = .018) increased urine output, it did not significantly improve renal function compared with placebo. There were no significant differences between the groups in the renal replacement therapy rate, the lengths of the intensive care unit and hospital stays, or medical costs. CONCLUSION Atrial natriuretic peptide infusion did not show a renoprotective effect or cost-saving effect in the treatment of cardiac surgery-associated AKI.
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Affiliation(s)
- Chieko Mitaka
- Department of Anesthesiology, Tokyo Medical and Dental University Hospital of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Anesthesiology and Pain Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan,.
| | - Tetsu Ohnuma
- Intensive Care Unit, Department of Anesthesiology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Ohmiya-ku, Saitama 330-8503, Japan.
| | - Takanori Murayama
- Intensive Care Unit, Department of Anesthesiology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Ohmiya-ku, Saitama 330-8503, Japan.
| | - Fumio Kunimoto
- Intensive Care Unit, Gunma University Hospital, 3-39-15 Shouwa, Maebashi, Gunma 371-8511, Japan.
| | - Michio Nagashima
- Intensive Care Unit, Yokohama City Minato Red Cross Hospital, 3-12-1 Shinyamashita, Naka-ku, Yokohama, Kanagawa 231-8682, Japan.
| | - Tetsuhiro Takei
- Intensive Care Unit, Yokohama City Minato Red Cross Hospital, 3-12-1 Shinyamashita, Naka-ku, Yokohama, Kanagawa 231-8682, Japan.
| | - Naoya Iguchi
- Intensive Care Unit, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Makoto Tomita
- Clinical Research Center, Tokyo Medical and Dental University Hospital of Medicine 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
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Morikis VA, Radecke C, Jiang Y, Heinrich V, Curry FR, Simon SI. Atrial natriuretic peptide down-regulates neutrophil recruitment on inflamed endothelium by reducing cell deformability and resistance to detachment force. Biorheology 2016; 52:447-63. [PMID: 26639357 DOI: 10.3233/bir-15067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Recombinant atrial natriuretic peptide (ANP) is administered in patients with acute heart failure in Japan to improve renal function and hemodynamics, but its anti-inflammatory effect on activated leukocytes may also contribute to its therapeutic efficacy. OBJECTIVE Examine unconventional role of ANP in neutrophil adhesion to inflamed endothelium. METHODS Human neutrophils were perfused over endothelial monolayers in a microfluidic lab-chip assay. Cell rheology was assessed by micropipette aspiration to assess changes in cortical tension and viscosity. Fluorescence microscopy was applied to measure adhesive contact area and β2-integrin focal bond formation. RESULTS ANP inhibited neutrophil rolling and firm adhesion without influencing the upregulation of cellular adhesion molecules on endothelium or the regulation of high affinity CD18 and shedding of L-selectin during neutrophil activation. Exposed to fluid shear, integrin mediated arrest was disrupted with ANP treatment, which elicited formation of long tethers and diminished cell spreading and contact. This correlated with a ∼40% increase in neutrophil viscosity and a reduction in the adhesive footprint. CONCLUSIONS A decrease in cell deformation and neutrophil flattening with ANP results in fewer integrin bond clusters, which translates to higher tensile forces and impaired adhesion strengthening and cell detachment.
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Affiliation(s)
- Vasilios A Morikis
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
| | - Chris Radecke
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
| | - Yanyan Jiang
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
| | - Volkmar Heinrich
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
| | - Fitz-Roy Curry
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA.,Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA 95616, USA
| | - Scott I Simon
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
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Curry FRE, Clark JF, Jiang Y, Kim MH, Adamson RH, Simon SI. The role of atrial natriuretic peptide to attenuate inflammation in a mouse skin wound and individually perfused rat mesenteric microvessels. Physiol Rep 2016; 4:4/18/e12968. [PMID: 27670406 PMCID: PMC5037917 DOI: 10.14814/phy2.12968] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 08/22/2016] [Indexed: 01/05/2023] Open
Abstract
We tested the hypothesis that the anti‐inflammatory actions of atrial natriuretic peptide (ANP) result from the modulation of leukocyte adhesion to inflamed endothelium and not solely ANP ligation of endothelial receptors to stabilize endothelial barrier function. We measured vascular permeability to albumin and accumulation of fluorescent neutrophils in a full‐thickness skin wound on the flank of LysM‐EGFP mice 24 h after formation. Vascular permeability in individually perfused rat mesenteric microvessels was also measured after leukocytes were washed out of the vessel lumen. Thrombin increased albumin permeability and increased the accumulation of neutrophils. The thrombin‐induced inflammatory responses were attenuated by pretreating the wound with ANP (30 min). During pretreatment ANP did not lower permeability, but transiently increased baseline albumin permeability concomitant with the reduction in neutrophil accumulation. ANP did not attenuate acute increases in permeability to histamine and bradykinin in individually perfused rat microvessels. The hypothesis that anti‐inflammatory actions of ANP depend solely on endothelial responses that stabilize the endothelial barrier is not supported by our results in either individually perfused microvessels in the absence of circulating leukocytes or the more chronic skin wound model. Our results conform to the alternate hypothesis that ANP modulates the interaction of leukocytes with the inflamed microvascular wall of the 24 h wound. Taken together with our previous observations that ANP reduces deformability of neutrophils and their strength of attachment, rolling, and transvascular migration, these observations provide the basis for additional investigations of ANP as an anti‐inflammatory agent to modulate leukocyte–endothelial cell interactions.
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Affiliation(s)
- Fitz-Roy E Curry
- Department of Physiology & Membrane Biology, University of California, Davis, Davis, California
| | - Joyce F Clark
- Department of Physiology & Membrane Biology, University of California, Davis, Davis, California
| | - Yanyan Jiang
- Department of Physiology & Membrane Biology, University of California, Davis, Davis, California
| | - Min-Ho Kim
- Department of Biomedical Engineering, University of California, Davis, Davis, California
| | - Roger H Adamson
- Department of Physiology & Membrane Biology, University of California, Davis, Davis, California
| | - Scott I Simon
- Department of Biomedical Engineering, University of California, Davis, Davis, California
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Chen W, Spitzl A, Mathes D, Nikolaev VO, Werner F, Weirather J, Špiranec K, Röck K, Fischer JW, Kämmerer U, Stegner D, Baba HA, Hofmann U, Frantz S, Kuhn M. Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction. Circ Res 2016; 119:237-48. [PMID: 27142162 DOI: 10.1161/circresaha.115.307196] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 03/03/2016] [Indexed: 12/21/2022]
Abstract
RATIONALE In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial natriuretic peptide (NP) and B-type NP, with their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation. OBJECTIVE We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI. METHODS AND RESULTS Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (knockout mice with endothelial GC-A deletion) or cGKI (knockout mice with endothelial cGKI deletion). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2 days after AMI were attenuated in knockout mice with endothelial GC-A deletion and unaltered in knockout mice with endothelial cGKI deletion. Molecular studies revealed that hypoxia and tumor necrosis factor-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase 2A (PDE2A) levels. Real-time cAMP measurements in endothelial microdomains using a novel fluorescence resonance energy transfer biosensor revealed that PDE2 mediates NP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that tumor necrosis factor-α-induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions. CONCLUSIONS Hypoxia and cytokines, such as tumor necrosis factor-α, modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A, and altered cGMP/cAMP cross talk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NP/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.
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Affiliation(s)
- Wen Chen
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Annett Spitzl
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Denise Mathes
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Viacheslav O Nikolaev
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Franziska Werner
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Johannes Weirather
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Katarina Špiranec
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Katharina Röck
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Jens W Fischer
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Ulrike Kämmerer
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - David Stegner
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Hideo A Baba
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Ulrich Hofmann
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Stefan Frantz
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.)
| | - Michaela Kuhn
- From the Institute of Physiology (W.C., A.S., F.W., K.Š., M.K.), Comprehensive Heart Failure Center (D.M., J.W., U.H., S.F., M.K.), and Department of Experimental Biomedicine and Rudolf Virchow Center for Experimental Biomedicine (D.S.), University of Würzburg, Würzburg, Germany; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (V.O.N.); Institut für Pharmakologie und Klinische Pharmakologie und CARID, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (K.R., J.W.F.); Department of Obstetrics and Gynecology, University Hospital Würzburg, Würzburg, Germany (U.K.); Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
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Chu LY, Wang YF, Cheng HH, Kuo CC, Wu KK. Endothelium-Derived 5-Methoxytryptophan Protects Endothelial Barrier Function by Blocking p38 MAPK Activation. PLoS One 2016; 11:e0152166. [PMID: 27002329 PMCID: PMC4803234 DOI: 10.1371/journal.pone.0152166] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 03/09/2016] [Indexed: 12/25/2022] Open
Abstract
The endothelial junction is tightly controlled to restrict the passage of blood cells and solutes. Disruption of endothelial barrier function by bacterial endotoxins, cytokines or growth factors results in inflammation and vascular damage leading to vascular diseases. We have identified 5-methoxytryptophan (5-MTP) as an anti-inflammatory factor by metabolomic analysis of conditioned medium of human fibroblasts. Here we postulated that endothelial cells release 5-MTP to protect the barrier function. Conditioned medium of human umbilical vein endothelial cells (HUVECs) prevented endothelial hyperpermeability and VE-cadherin downregulation induced by VEGF, LPS and cytokines. We analyzed the metabolomic profile of HUVEC conditioned medium and detected 5-MTP but not melatonin, serotonin or their catabolites, which was confirmed by enzyme-linked immunosorbent assay. Addition of synthetic pure 5-MTP preserved VE-cadherin and maintained barrier function despite challenge with pro-inflammatory mediators. Tryptophan hydroxylase-1, an enzyme required for 5-MTP biosynthesis, was downregulated in HUVECs by pro-inflammatory mediators and it was accompanied by reduction of 5-MTP. 5-MTP protected VE-cadherin and prevented endothelial hyperpermeability by blocking p38 MAPK activation. A chemical inhibitor of p38 MAPK, SB202190, exhibited a similar protective effect as 5-MTP. To determine whether 5-MTP prevents vascular hyperpermeability in vivo, we evaluated the effect of 5-MTP administration on LPS-induced murine microvascular permeability with Evans blue. 5-MTP significantly prevented Evans blue dye leakage. Our findings indicate that 5-MTP is a new class of endothelium-derived molecules which protects endothelial barrier function by blocking p38 MAPK.
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Affiliation(s)
- Ling-Yun Chu
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Fu Wang
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Huei-Hsuan Cheng
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Cheng-Chin Kuo
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Kenneth K. Wu
- Metabolomic Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
- Department of Medical Sciences and Institute of Biotechnology National TsingHua University, Hsinchu, Taiwan
- * E-mail:
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Farwell SLN, Kanyi D, Hamel M, Slee JB, Miller EA, Cipolle MD, Lowe-Krentz LJ. Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1. J Biol Chem 2016; 291:5342-54. [PMID: 26769965 DOI: 10.1074/jbc.m115.681288] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Indexed: 11/06/2022] Open
Abstract
Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparin-induced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNFα-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNFα-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity.
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Affiliation(s)
- Sara Lynn N Farwell
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015
| | - Daniela Kanyi
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, the Department of Chemistry, Lehigh University, Allentown, Pennsylvania 18103
| | - Marianne Hamel
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015
| | - Joshua B Slee
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, the Department of Natural Sciences, DeSales University, Center Valley, Pennsylvania 18034
| | - Elizabeth A Miller
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015
| | - Mark D Cipolle
- the Department of Surgery, Lehigh Valley Hospital Center, Allentown, Pennsylvania 18103, and
| | - Linda J Lowe-Krentz
- From the Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015,
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Doggett TM, Breslin JW. Acute alcohol intoxication-induced microvascular leakage. Alcohol Clin Exp Res 2015; 38:2414-26. [PMID: 25257290 DOI: 10.1111/acer.12525] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 07/02/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Alcohol intoxication can increase inflammation and worsen injury, yet the mechanisms involved are not clear. We investigated whether acute alcohol intoxication increases microvascular permeability and investigated potential signaling mechanisms in endothelial cells that may be involved. METHODS Conscious rats received a 2.5 g/kg alcohol bolus via gastric catheters to produce acute intoxication. Microvascular leakage of intravenously administered fluorescein isothiocyanate (FITC)-conjugated albumin (FITC-albumin) from the mesenteric microcirculation was assessed by intravital microscopy. Endothelial-specific mechanisms were studied using cultured endothelial cell monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function, before and after treatment with alcohol or its metabolite acetaldehyde. Pharmacologic agents were used to test the roles of alcohol metabolism, oxidative stress, p38 mitogen-activated protein kinase (MAPK), myosin light-chain kinase (MLCK), rho kinase (ROCK), and exchange protein activated by cAMP (Epac). VE-cadherin localization was investigated to assess junctional integrity. Rac1 and RhoA activation was assessed by ELISA assays. RESULTS Alcohol significantly increased FITC-albumin extravasation from the mesenteric microcirculation. Alcohol also significantly decreased TER and disrupted VE-cadherin organization at junctions. Acetaldehyde significantly decreased TER, but inhibition of alcohol dehydrogenase or application of a superoxide dismutase mimetic failed to prevent alcohol-induced decreases in TER. Inhibition of p38 MAPK, but not MLCK or ROCK, significantly attenuated the alcohol-induced barrier dysfunction. Alcohol rapidly decreased GTP-bound Rac1 but not RhoA during the drop in TER. Activation of Epac increased TER, but did not prevent alcohol from decreasing TER. However, activation of Epac after initiation of alcohol-induced barrier dysfunction quickly resolved TER to baseline levels. CONCLUSIONS Our results suggest that alcohol intoxication increases microvascular permeability to plasma proteins. The data also suggest the endothelial-specific mechanism involves the p38 MAPK, Rac1, and reorganization of VE-cadherin at junctions. Last, activation of Epac can quickly resolve alcohol-induced endothelial barrier dysfunction.
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Affiliation(s)
- Travis M Doggett
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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Hoppstädter J, Kessler SM, Bruscoli S, Huwer H, Riccardi C, Kiemer AK. Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance. THE JOURNAL OF IMMUNOLOGY 2015; 194:6057-6067. [DOI: 10.4049/jimmunol.1403207] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.
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Affiliation(s)
- Jessica Hoppstädter
- *Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany
| | - Sonja M. Kessler
- *Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany
| | - Stefano Bruscoli
- †Section of Pharmacology, Department of Medicine, University of Perugia, 06100 Perugia, Italy; and
| | - Hanno Huwer
- ‡Department of Cardiothoracic Surgery, Völklingen Heart Centre, 66333 Völklingen, Germany
| | - Carlo Riccardi
- †Section of Pharmacology, Department of Medicine, University of Perugia, 06100 Perugia, Italy; and
| | - Alexandra K. Kiemer
- *Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany
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Li L, Dong F, Xu D, Du L, Yan S, Hu H, Lobe CG, Yi F, Kapron CM, Liu J. Short-term, low-dose cadmium exposure induces hyperpermeability in human renal glomerular endothelial cells. J Appl Toxicol 2015; 36:257-65. [PMID: 26011702 DOI: 10.1002/jat.3168] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 03/21/2015] [Accepted: 04/07/2015] [Indexed: 12/27/2022]
Affiliation(s)
- Liqun Li
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | - Fengyun Dong
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | - Dongmei Xu
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | - Linna Du
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | - Suhua Yan
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | - Hesheng Hu
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
| | | | - Fan Yi
- Department of Pharmacology; Shandong University School of Medicine; Jinan Shandong China
| | - Carolyn M. Kapron
- Department of Biology; Trent University; Peterborough Ontario Canada
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital; Shandong University; Jinan Shandong China
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Passaglia P, Ceron CS, Mecawi AS, Antunes-Rodrigues J, Coelho EB, Tirapelli CR. Angiotensin type 1 receptor mediates chronic ethanol consumption-induced hypertension and vascular oxidative stress. Vascul Pharmacol 2015; 74:49-59. [PMID: 25872164 DOI: 10.1016/j.vph.2015.04.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 03/09/2015] [Accepted: 04/04/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVES We hypothesized that chronic ethanol intake enhances vascular oxidative stress and induces hypertension through renin-angiotensin system (RAS) activation. METHODS AND RESULTS Male Wistar rats were treated with ethanol (20% v/v). The increase in blood pressure induced by ethanol was prevented by losartan (10mg/kg/day; p.o. gavage), a selective AT1 receptor antagonist. Chronic ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels and serum aldosterone levels. No differences on plasma osmolality and sodium or potassium levels were detected after treatment with ethanol. Ethanol consumption did not alter ACE activity, as well as the levels of ANG I and ANG II in the rat aorta or mesenteric arterial bed (MAB). Ethanol induced systemic and vascular oxidative stress (aorta and MAB) and these effects were prevented by losartan. The decrease on plasma and vascular nitrate/nitrite (NOx) levels induced by ethanol was prevented by losartan. Ethanol intake did not alter protein expression of ACE, AT1 or AT2 receptors in both aorta and MAB. Aortas from ethanol-treated rats displayed decreased ERK1/2 phosphorylation and increased protein expression of SAPK/JNK. These responses were prevented by losartan. MAB from ethanol-treated rats displayed reduced phosphorylation of p38MAPK and ERK1/2 and losartan did not prevent these responses. CONCLUSIONS Our study provides novel evidence that chronic ethanol intake increases blood pressure, induces vascular oxidative stress and decreases nitric oxide (NO) bioavailability through AT1-dependent mechanisms.
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Affiliation(s)
- Patrícia Passaglia
- Programa de pós-graduação em Toxicologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Escola de Enfermagem de Ribeirão Preto, Laboratório de Farmacologia, USP, Ribeirão Preto, São Paulo, Brazil
| | - Carla S Ceron
- Escola de Enfermagem de Ribeirão Preto, Laboratório de Farmacologia, USP, Ribeirão Preto, São Paulo, Brazil
| | - André S Mecawi
- Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | | | - Eduardo B Coelho
- Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Carlos R Tirapelli
- Escola de Enfermagem de Ribeirão Preto, Laboratório de Farmacologia, USP, Ribeirão Preto, São Paulo, Brazil.
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Della Penna SL, Rosón MI, Toblli JE, Fernández BE. Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia: Benefits of atrial natriuretic peptide, losartan, and tempol. Free Radic Res 2015; 49:383-96. [DOI: 10.3109/10715762.2015.1006216] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system. JOURNAL OF SIGNAL TRANSDUCTION 2014; 2014:731350. [PMID: 25436148 PMCID: PMC4243602 DOI: 10.1155/2014/731350] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 10/16/2014] [Indexed: 12/24/2022]
Abstract
The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation.
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Mitaka C, Si MKH, Tulafu M, Yu Q, Uchida T, Abe S, Kitagawa M, Ikeda S, Eishi Y, Tomita M. Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury. Intensive Care Med Exp 2014; 2:28. [PMID: 26266925 PMCID: PMC4513012 DOI: 10.1186/s40635-014-0028-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 10/22/2014] [Indexed: 01/09/2023] Open
Abstract
Background Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. Renal IRI releases proinflammatory cytokines within the kidney that induce crosstalk between the kidney and other organ systems. Atrial natriuretic peptide (ANP) has anti-inflammatory as well as natriuretic effects and serves important functions as a regulator of blood pressure, fluid homeostasis, and inflammation. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI. Methods In experiment I, a rat model of unilateral renal IRI with mechanical ventilation was prepared by clamping the left renal pedicle for 30 min. Five minutes after clamping, saline or ANP (0.2 μg/kg/min) was infused. The hemodynamics, arterial blood gases, and plasma concentrations of lactate and potassium were measured at baseline and at 1, 2, and 3 h after declamping. The mRNA expression and localization of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the kidney, lung, and heart were examined. In experiment II, a rat model of bilateral renal IRI without mechanical ventilation was prepared by clamping bilateral renal pedicles for 30 min. Thirty minutes after clamping, lactated Ringer's (LR) solution or ANP (0.2 μg/kg/min) was infused. Plasma concentrations of TNF-α, IL-6, and IL-1β were determined at baseline and at 3 h after declamping. Results In unilateral IRI rats with mechanical ventilation, ANP inhibited the following changes induced by IRI: metabolic acidosis; pulmonary edema; increases in lactate, creatinine, and potassium; and increases in the mRNA expression of TNF-α, IL-1β, and IL-6 in the kidney and lung and IL-1β and IL-6 in the heart. It also attenuated the histological localization of TNF-α, IL-6, and nuclear factor (NF)-κB in the kidney and lung. In bilateral IRI rats without mechanical ventilation, ANP attenuated the IRI-induced increases of the plasma concentrations of potassium, IL-1β, and IL-6. Conclusions Renal IRI induced injury in remote organs including the lung and the contralateral kidney. ANP post-treatment ameliorated injuries in these organs by direct tissue protective effect and anti-inflammatory effects, which potentially inhibited inter-organ crosstalk.
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Affiliation(s)
- Chieko Mitaka
- Department of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan,
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Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production. Acta Biomater 2014; 10:4896-4911. [PMID: 25123083 DOI: 10.1016/j.actbio.2014.07.027] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 06/26/2014] [Accepted: 07/22/2014] [Indexed: 01/08/2023]
Abstract
Superparamagnetic iron oxide nanoparticles (SPION) are widely used both clinically and experimentally for diverse in vivo applications, such as contrast enhancement in magnetic resonance imaging, hyperthermia and drug delivery. Biomedical applications require particles to have defined physical and chemical properties, and to be stable in biological media. Despite a suggested low cytotoxic action, adverse reactions of SPION in concentrations relevant for biomedical use have not yet been studied in sufficient detail. In the present work we employed Endorem®, dextran-stabilized SPION approved as an intravenous contrast agent, and compared its action to a set of other nanoparticles with potential for magnetic resonance imaging applications. SPION in concentrations relevant for in vivo applications were rapidly taken up by endothelial cells and exhibited no direct cytotoxicity. Electric cell impedance sensing measurements demonstrated that SPION, but not BaSO4/Gd nanoparticles, impaired endothelial integrity, as was confirmed by increased intercellular gap formation in endothelial monolayers. These structural changes induced the subcellular translocation and inhibition of the cytoprotective and anti-atherosclerotic enzyme endothelial NO-synthase and reduced NO production. Lipopolysaccharide-induced inflammatory NO production of macrophages was not affected by SPION. In conclusion, our data suggest that SPION might substantially alter endothelial integrity and function at therapeutically relevant doses, which are not cytotoxic.
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Vandendriessche B, Goethals A, Simats A, Van Hamme E, Brouckaert P, Cauwels A. MAPK-activated protein kinase 2-deficiency causes hyperacute tumor necrosis factor-induced inflammatory shock. BMC PHYSIOLOGY 2014; 14:5. [PMID: 25185746 PMCID: PMC4160542 DOI: 10.1186/s12899-014-0005-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 08/04/2014] [Indexed: 02/08/2023]
Abstract
Background MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/d-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases. Results We show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis. Conclusions The capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account.
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Affiliation(s)
| | | | | | | | | | - Anje Cauwels
- Inflammation Research Center, VIB, Ghent, 9052, Belgium.
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De Vito P. Atrial natriuretic peptide: an old hormone or a new cytokine? Peptides 2014; 58:108-16. [PMID: 24973596 DOI: 10.1016/j.peptides.2014.06.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 06/19/2014] [Accepted: 06/19/2014] [Indexed: 02/07/2023]
Abstract
Atrial natriuretic peptide (ANP) a cardiovascular hormone mainly secreted by heart atria in response to stretching forces induces potent diuretic, natriuretic and vasorelaxant effects and plays a major role in the homeostasis of blood pressure as well as of water and salt balance. The hormone can also act as autocrine/paracrine factor and modulate several immune functions as well as cytoprotective effects. ANP contributes to innate immunity being able to: (i) stimulate the host defense against extracellular microbes by phagocytosis and Reactive Oxygen Species (ROS) release; (ii) inhibit the synthesis and release of proinflammatory markers such as TNF-α, IL-1, MCP-1, nitric oxide (NO), cyclooxygenase-2 (COX-2); (iii) inhibit the expression of adhesion molecules such as ICAM-1 and E-selectin. ANP can also affect the adaptive immunity being able to: (i) reduce the number of CD4(+) CD8(+) lymphocytes as well as to increase the CD4(-) CD8(-) cells; (ii) stimulate the differentiation of naïve CD4(+) cells toward the Th2 and/or Th17 phenotype. The hormone shows protective effects during: (i) ventricular hypertrophy and myocardial injury; (ii) atherosclerosis and hypertension by the induction of antiproliferative effects; (iii) oxidative stress counteracting the dangerous effects of ROS; (iv) growth of tumors cells by the induction of apoptosis or necrosis. Since not much is known about of the role of ANP locally produced and released by non-cardiac cells, this review outlines the contribution of ANP in different aspect of innate as well as adaptive immunity also with respect to the excessive cell growth in physiological and/or pathological conditions.
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Affiliation(s)
- Paolo De Vito
- Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.
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Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci 2014; 341:88-96. [DOI: 10.1016/j.jns.2014.04.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 04/01/2014] [Accepted: 04/03/2014] [Indexed: 11/18/2022]
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