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OUP accepted manuscript. Nutr Rev 2022; 80:2002-2016. [DOI: 10.1093/nutrit/nuac019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Herranz C, Mateo F, Baiges A, Ruiz de Garibay G, Junza A, Johnson SR, Miller S, García N, Capellades J, Gómez A, Vidal A, Palomero L, Espín R, Extremera AI, Blommaert E, Revilla‐López E, Saez B, Gómez‐Ollés S, Ancochea J, Valenzuela C, Alonso T, Ussetti P, Laporta R, Xaubet A, Rodríguez‐Portal JA, Montes‐Worboys A, Machahua C, Bordas J, Menendez JA, Cruzado JM, Guiteras R, Bontoux C, La Motta C, Noguera‐Castells A, Mancino M, Lastra E, Rigo‐Bonnin R, Perales JC, Viñals F, Lahiguera A, Zhang X, Cuadras D, van Moorsel CHM, van der Vis JJ, Quanjel MJR, Filippakis H, Hakem R, Gorrini C, Ferrer M, Ugun‐Klusek A, Billett E, Radzikowska E, Casanova Á, Molina‐Molina M, Roman A, Yanes O, Pujana MA. Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis. EMBO Mol Med 2021; 13:e13929. [PMID: 34378323 PMCID: PMC8422079 DOI: 10.15252/emmm.202113929] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 11/12/2022] Open
Abstract
Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
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Affiliation(s)
- Carmen Herranz
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Francesca Mateo
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Alexandra Baiges
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Gorka Ruiz de Garibay
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Alexandra Junza
- Department of Electronic EngineeringInstitute of Health Research Pere Virgili (IIPSV)University Rovira i VirgiliTarragonaSpain
- Biomedical Research Network Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)Instituto de Salud Carlos IIIMadridSpain
| | - Simon R Johnson
- National Centre for LymphangioleiomyomatosisNottingham University Hospitals NHS Trust, NottinghamshireDivision of Respiratory MedicineUniversity of NottinghamNottinghamUK
| | - Suzanne Miller
- National Centre for LymphangioleiomyomatosisNottingham University Hospitals NHS Trust, NottinghamshireDivision of Respiratory MedicineUniversity of NottinghamNottinghamUK
| | - Nadia García
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Jordi Capellades
- Department of Electronic EngineeringInstitute of Health Research Pere Virgili (IIPSV)University Rovira i VirgiliTarragonaSpain
- Biomedical Research Network Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)Instituto de Salud Carlos IIIMadridSpain
| | - Antonio Gómez
- Centre for Genomic RegulationBarcelona Institute of Science and TechnologyBarcelonaSpain
- Present address:
Rheumatology Department and Rheumatology Research GroupVall d'Hebron Hospital Research Institute (VHIR)BarcelonaSpain
| | - August Vidal
- Department of PathologyUniversity Hospital of BellvitgeOncobellIDIBELL, L’Hospitalet del LlobregatBarcelonaSpain
- CIBER on Cancer (CIBERONC)Instituto de Salud Carlos IIIMadridSpain
| | - Luis Palomero
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Roderic Espín
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Ana I Extremera
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Eline Blommaert
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Eva Revilla‐López
- Lung Transplant Unit, Pneumology ServiceLymphangioleiomyomatosis ClinicVall d’Hebron University HospitalBarcelonaSpain
| | - Berta Saez
- Lung Transplant Unit, Pneumology ServiceLymphangioleiomyomatosis ClinicVall d’Hebron University HospitalBarcelonaSpain
| | - Susana Gómez‐Ollés
- Lung Transplant Unit, Pneumology ServiceLymphangioleiomyomatosis ClinicVall d’Hebron University HospitalBarcelonaSpain
| | - Julio Ancochea
- Pneumology ServiceLa Princesa Research InstituteUniversity Hospital La PrincesaMadridSpain
| | - Claudia Valenzuela
- Pneumology ServiceLa Princesa Research InstituteUniversity Hospital La PrincesaMadridSpain
| | - Tamara Alonso
- Pneumology ServiceLa Princesa Research InstituteUniversity Hospital La PrincesaMadridSpain
| | - Piedad Ussetti
- Pneumology ServiceUniversity Hospital Clínica Puerta del Hierro, MajadahondaMadridSpain
| | - Rosalía Laporta
- Pneumology ServiceUniversity Hospital Clínica Puerta del Hierro, MajadahondaMadridSpain
| | - Antoni Xaubet
- Pneumology ServiceHospital Clínic de BarcelonaBarcelonaSpain
| | - José A Rodríguez‐Portal
- Medical‐Surgical Unit of Respiratory DiseasesInstitute of Biomedicine of Seville (IBiS)University Hospital Virgen del RocíoSevilleSpain
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES)Instituto de Salud Carlos IIIMadridSpain
| | - Ana Montes‐Worboys
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES)Instituto de Salud Carlos IIIMadridSpain
- Interstitial Lung Disease UnitDepartment of Respiratory MedicineUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Carlos Machahua
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES)Instituto de Salud Carlos IIIMadridSpain
- Interstitial Lung Disease UnitDepartment of Respiratory MedicineUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Jaume Bordas
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES)Instituto de Salud Carlos IIIMadridSpain
- Interstitial Lung Disease UnitDepartment of Respiratory MedicineUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Javier A Menendez
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Josep M Cruzado
- Experimental NephrologyDepartment of Clinical SciencesUniversity of BarcelonaBarcelonaSpain
- Department of NephrologyUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Roser Guiteras
- Experimental NephrologyDepartment of Clinical SciencesUniversity of BarcelonaBarcelonaSpain
- Department of NephrologyUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Christophe Bontoux
- Department of PathologyUniversity Hospital Pitié‐SalpêtrièreFaculty of MedicineUniversity of SorbonneParisFrance
| | | | - Aleix Noguera‐Castells
- Biomedical Research Institute “August Pi i Sunyer” (IDIBAPS)Department of MedicineUniversity of BarcelonaBarcelonaSpain
| | - Mario Mancino
- Biomedical Research Institute “August Pi i Sunyer” (IDIBAPS)Department of MedicineUniversity of BarcelonaBarcelonaSpain
| | - Enrique Lastra
- Genetic Counseling UnitDepartment of Medical OncologyUniversity Hospital of BurgosBurgosSpain
| | - Raúl Rigo‐Bonnin
- Clinical LaboratoryUniversity Hospital of BellvitgeIDIBELLL'Hospitalet de LlobregatBarcelonaSpain
| | - Jose C Perales
- Department of Physiological Science IIUniversity of BarcelonaBarcelonaSpain
| | - Francesc Viñals
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
- Department of Physiological Science IIUniversity of BarcelonaBarcelonaSpain
| | - Alvaro Lahiguera
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
| | - Xiaohu Zhang
- National Center for Advancing Translational Sciences (NCATS)National Institute of Health (NIH)BethesdaMDUSA
| | - Daniel Cuadras
- Statistics DepartmentFoundation Sant Joan de DéuEspluguesSpain
| | - Coline H M van Moorsel
- Interstitial Lung Disease (ILD) Center of ExcellenceSt. Antonius HospitalNieuwegeinThe Netherlands
| | - Joanne J van der Vis
- Interstitial Lung Disease (ILD) Center of ExcellenceSt. Antonius HospitalNieuwegeinThe Netherlands
| | - Marian J R Quanjel
- Interstitial Lung Disease (ILD) Center of ExcellenceSt. Antonius HospitalNieuwegeinThe Netherlands
| | - Harilaos Filippakis
- Pulmonary and Critical Care MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA
| | - Razq Hakem
- Princess Margaret Cancer CentreUniversity Health NetworkDepartment of Medical BiophysicsUniversity of TorontoTorontoOntarioCanada
| | - Chiara Gorrini
- Princess Margaret HospitalThe Campbell Family Institute for Breast Cancer ResearchOntario Cancer InstituteUniversity Health NetworkTorontoONCanada
| | - Marc Ferrer
- National Center for Advancing Translational Sciences (NCATS)National Institute of Health (NIH)BethesdaMDUSA
| | - Aslihan Ugun‐Klusek
- Centre for Health, Ageing and Understanding Disease (CHAUD)School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - Ellen Billett
- Centre for Health, Ageing and Understanding Disease (CHAUD)School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - Elżbieta Radzikowska
- Department of Lung Diseases IIINational Tuberculosis and Lung Disease Research InstituteWarsawPoland
| | - Álvaro Casanova
- Pneumology ServiceUniversity Hospital of HenaresUniversity Francisco de Vitoria, CosladaMadridSpain
| | - María Molina‐Molina
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES)Instituto de Salud Carlos IIIMadridSpain
- Interstitial Lung Disease UnitDepartment of Respiratory MedicineUniversity Hospital of BellvitgeIDIBELLL’Hospitalet del LlobregatBarcelonaSpain
| | - Antonio Roman
- Lung Transplant Unit, Pneumology ServiceLymphangioleiomyomatosis ClinicVall d’Hebron University HospitalBarcelonaSpain
| | - Oscar Yanes
- Department of Electronic EngineeringInstitute of Health Research Pere Virgili (IIPSV)University Rovira i VirgiliTarragonaSpain
- Biomedical Research Network Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)Instituto de Salud Carlos IIIMadridSpain
| | - Miquel A Pujana
- ProCURECatalan Institute of OncologyOncobellBellvitge Institute for Biomedical Research (IDIBELL)L’Hospitalet del LlobregatBarcelonaSpain
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de Seabra Rodrigues Dias IR, Mok SWF, Gordillo-Martínez F, Khan I, Hsiao WWL, Law BYK, Wong VKW, Liu L. The Calcium-Induced Regulation in the Molecular and Transcriptional Circuitry of Human Inflammatory Response and Autoimmunity. Front Pharmacol 2018; 8:962. [PMID: 29358919 PMCID: PMC5766673 DOI: 10.3389/fphar.2017.00962] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 12/18/2017] [Indexed: 01/01/2023] Open
Abstract
Rheumatoid arthritis synovial fibroblasts (RASFs) are fundamental effector cells in RA driving the joint inflammation and deformities. Celastrol is a natural compound that exhibits a potent anti-arthritic effect promoting endoplasmic reticulum (ER) stress mediated by intracellular calcium (Ca2+) mobilization. Ca2+ is a second messenger regulating a variety of cellular processes. We hypothesized that the compound, celastrol, affecting cytosolic Ca2+ mobilization could serve as a novel strategy to combat RA. To address this issue, celastrol was used as a molecular tool to assay the inflammatory gene expression profile regulated by Ca2+. We confirmed that celastrol treatment mobilized cytosolic Ca2+ in patient-derived RASFs. It was found that 23 genes out of 370 were manipulated by Ca2+ mobilization using an inflammatory and autoimmunity PCR array following independent quantitative PCR validation. Most of the identified genes were downregulated and categorized into five groups corresponding to their cellular responses participating in RA pathogenesis. Accordingly, a signaling network map demonstrating the possible molecular circuitry connecting the functions of the products of these genes was generated based on literature review. In addition, a bioinformatics analysis revealed that celastrol-induced Ca2+ mobilization gene expression profile showed a novel mode of action compared with three FDA-approved rheumatic drugs (methotrexate, rituximab and tocilizumab). To the best of our knowledge, this is a pioneer work charting the Ca2+ signaling network on the regulation of RA-associated inflammatory gene expression.
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Affiliation(s)
| | - Simon W F Mok
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Flora Gordillo-Martínez
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Imran Khan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Wendy W L Hsiao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Betty Y K Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Vincent K W Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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Johnson C, Hargrove L, Graf A, Kennedy L, Hodges K, Harris R, Francis T, Ueno Y, Francis H. Histamine restores biliary mass following carbon tetrachloride-induced damage in a cholestatic rat model. Dig Liver Dis 2015; 47:211-7. [PMID: 25575430 DOI: 10.1016/j.dld.2014.12.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 12/01/2014] [Accepted: 12/06/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Bile duct ligation coupled with carbon tetrachloride induces apoptosis of large but not small cholangiocytes. Histidine decarboxylase regulates histamine synthesis. We have shown that: (i) cholangiocytes express histidine decarboxylase and secrete histamine and (ii) histamine stimulates biliary growth. AIMS To demonstrate that histidine decarboxylase/histamine regulates cholangiocyte homeostasis after carbon tetrachloride treatment. METHODS In vivo, normal and bile duct ligated rats were treated with saline or histamine (0.5mg/kg body weight) and given carbon tetrachloride by gavage 2 days before sacrifice. Serum, liver blocks and large cholangiocytes were obtained. Histidine decarboxylase, bile duct mass and proliferation were measured in liver sections and in cholangiocytes. Apoptosis was measured by immunohistochemistry and gene expression. Histamine levels were evaluated in serum. In vitro, large cholangiocytes were treated with carbon tetrachloride in the absence/presence of histamine before evaluating proliferation. RESULTS After bile duct ligation there was enhanced ductal mass, histidine decarboxylase expression and serum histamine levels. Carbon tetrachloride treatment enhanced biliary apoptosis, and decreased histidine decarboxylase and serum histamine levels and biliary proliferation, changes that were restored by histamine. In vitro, cholangiocytes treated with carbon tetrachloride had a lower proliferative capacity that was reversed when cells were pre-treated with histamine. CONCLUSION Histidine decarboxylase may be a key regulator of cholangiocyte homeostasis during biliary injury.
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Affiliation(s)
| | - Laura Hargrove
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Allyson Graf
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Lindsey Kennedy
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Kyle Hodges
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Rachel Harris
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Taylor Francis
- Scott & White Digestive Disease Research Center, BaylorScott and White, USA
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Japan; CREST, Japan Science and Technology Agency, Japan
| | - Heather Francis
- Research, Central Texas Veteran's Health Care System, USA; Scott & White Digestive Disease Research Center, BaylorScott and White, USA; Medicine, Texas A&M University HSC, Temple, TX, USA.
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Francis HL, DeMorrow S, Franchitto A, Venter JK, Mancinelli RA, White MA, Meng F, Ueno Y, Carpino G, Renzi A, Baker KK, Shine HE, Francis TC, Gaudio E, Alpini GD, Onori P. Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms. J Transl Med 2012; 92:282-94. [PMID: 22064319 PMCID: PMC3293651 DOI: 10.1038/labinvest.2011.158] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts.
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Affiliation(s)
- Heather L Francis
- Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division of Research and Education, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Sharon DeMorrow
- Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Internal Medicine and Orthopedics Sciences, ‘La Sapienza’, Rome, Italy,Eleonora Lonillard Spencer Cenci Foundation, Rome, Italy
| | - Julie K Venter
- Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Romina A Mancinelli
- Department of Anatomical, Histological, Forensic Internal Medicine and Orthopedics Sciences, ‘La Sapienza’, Rome, Italy
| | - Mellanie A White
- Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Fanyin Meng
- Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division of Research and Education, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Yoshiyuki Ueno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Guido Carpino
- Department Health Science, University of Rome‘Foro Italico’, Italy
| | - Anastasia Renzi
- Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Department of Anatomical, Histological, Forensic Internal Medicine and Orthopedics Sciences, ‘La Sapienza’, Rome, Italy
| | - Kimberly K Baker
- Division of Research and Education, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Hannah E Shine
- Division of Research and Education, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Taylor C Francis
- Division of Research and Education, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Internal Medicine and Orthopedics Sciences, ‘La Sapienza’, Rome, Italy
| | - Gianfranco D Alpini
- Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division of Gastroenterology, Department of Medicine, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA,Division Research, Central Texas Veterans Health Care System, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Paolo Onori
- Department of Experimental Medicine, State University of L’Aquila, L’Aquila, Italy
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Francis H, Glaser S, Demorrow S, Gaudio E, Ueno Y, Venter J, Dostal D, Onori P, Franchitto A, Marzioni M, Vaculin S, Vaculin B, Katki K, Stutes M, Savage J, Alpini G. Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. Am J Physiol Cell Physiol 2008; 295:C499-513. [PMID: 18508907 DOI: 10.1152/ajpcell.00369.2007] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cholangiopathies are characterized by the heterogeneous proliferation of different-sized cholangiocytes. Large cholangiocytes proliferate by a cAMP-dependent mechanism. The function of small cholangiocytes may depend on the activation of inositol trisphosphate (IP(3))/Ca(2+)-dependent signaling pathways; however, data supporting this speculation are lacking. Four histamine receptors exist (HRH1, HRH2, HRH3, and HRH4). In several cells: 1) activation of HRH1 increases intracellular Ca(2+) concentration levels; and 2) increased [Ca(2+)](i) levels are coupled with calmodulin-dependent stimulation of calmodulin-dependent protein kinase (CaMK) and activation of cAMP-response element binding protein (CREB). HRH1 agonists modulate small cholangiocyte proliferation by activation of IP(3)/Ca(2+)-dependent CaMK/CREB. We evaluated HRH1 expression in cholangiocytes. Small and large cholangiocytes were stimulated with histamine trifluoromethyl toluidide (HTMT dimaleate; HRH1 agonist) for 24-48 h with/without terfenadine, BAPTA/AM, or W7 before measuring proliferation. Expression of CaMK I, II, and IV was evaluated in small and large cholangiocytes. We measured IP(3), Ca(2+) and cAMP levels, phosphorylation of CaMK I, and activation of CREB (in the absence/presence of W7) in small cholangiocytes treated with HTMT dimaleate. CaMK I knockdown was performed in small cholangiocytes stimulated with HTMT dimaleate before measurement of proliferation and CREB activity. Small and large cholangiocytes express HRH1, CaMK I, and CaMK II. Small (but not large) cholangiocytes proliferate in response to HTMT dimaleate and are blocked by terfenadine (HRH1 antagonist), BAPTA/AM, and W7. In small cholangiocytes, HTMT dimaleate increased IP(3)/Ca(2+) levels, CaMK I phosphorylation, and CREB activity. Gene knockdown of CaMK I ablated the effects of HTMT dimaleate on small cholangiocyte proliferation and CREB activation. The IP(3)/Ca(2+)/CaMK I/CREB pathway is important in the regulation of small cholangiocyte function.
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Affiliation(s)
- Heather Francis
- Central Texas Veterans Health Care System, Scott & White and Texas A&M Health Science Center College of Medicine, Medical Research Bldg., 702 SW H.K. Dodgen Loop, Temple, TX, 76504, USA
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7
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Demorrow S, Francis H, Alpini G. Biogenic amine actions on cholangiocyte function. Exp Biol Med (Maywood) 2007; 232:1005-13. [PMID: 17720946 DOI: 10.3181/0703-mr-51] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Biogenic amines, such as serotonin, histamine, dopamine, and the catecholamines epinephrine and norepinephrine, regulate a multitude of cellular responses. A great deal of effort has been invested into understanding the effects of these molecules and their corresponding receptor systems on cholangiocyte secretion, apoptosis, and growth. This review summarizes the results of these efforts and highlights the importance of these regulatory molecules on the physiology and pathophysiology of cholangiocytes.
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Affiliation(s)
- Sharon Demorrow
- The Division of Research and Education, Medical Research Building, Scott and White Hospital, 702 S.W. H.K. Dodgen Loop, Temple, TX 76504,USA.
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Francis H, Franchitto A, Ueno Y, Glaser S, DeMorrow S, Venter J, Gaudio E, Alvaro D, Fava G, Marzioni M, Vaculin B, Alpini G. H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. J Transl Med 2007; 87:473-87. [PMID: 17334413 PMCID: PMC3751000 DOI: 10.1038/labinvest.3700533] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Galpha(i/o) proteins reducing adenosine 3', 5'-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.
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MESH Headings
- Animals
- Bile Ducts/surgery
- Bile Ducts, Intrahepatic/drug effects
- Bile Ducts, Intrahepatic/growth & development
- Bile Ducts, Intrahepatic/pathology
- Cell Proliferation/drug effects
- Cyclic AMP/metabolism
- Cyclic AMP-Dependent Protein Kinases
- Disease Models, Animal
- Down-Regulation/drug effects
- Drug Therapy, Combination
- Gene Expression Regulation, Enzymologic/drug effects
- Histamine/pharmacology
- Histamine Agonists/pharmacology
- Hyperplasia/chemically induced
- Hyperplasia/pathology
- Ligation
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- MAP Kinase Signaling System
- Male
- Methylhistamines/pharmacology
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/metabolism
- Mitogen-Activated Protein Kinases/metabolism
- Phosphorylation
- Piperidines/pharmacology
- Protein Serine-Threonine Kinases/metabolism
- Rats
- Rats, Inbred F344
- Receptor, EphA8/metabolism
- Receptors, Histamine H3/genetics
- Receptors, Histamine H3/metabolism
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Affiliation(s)
- Heather Francis
- Department of Research and Education, College of Medicine, Scott & White Hospital and The Texas A & M University System Health Science Center, Temple, TX 76504, USA
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9
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Van Kolen K, Gilany K, Moens L, Esmans EL, Slegers H. P2Y12 receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1. Cell Signal 2006; 18:1169-81. [PMID: 16236484 DOI: 10.1016/j.cellsig.2005.09.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Accepted: 09/09/2005] [Indexed: 01/22/2023]
Abstract
Previously it was shown that stimulation of the P2Y12 receptor activates PKB signalling in C6 glioma cells [K. Van Kolen and H. Slegers, J. Neurochem. 89, 442.]. In the present study, the mechanisms involved in this response were further elucidated. In cells transfected with the Gbetagamma-scavenger beta-ARK1/GRK2 or Rap1GAPII, stimulation with 2MeSADP failed to enhance PKB phosphorylation demonstrating that the signalling proceeds through Gbetagamma-subunits and Rap1. Moreover, Rap1-GTP pull-down assays revealed that P2Y12 receptor stimulation induced a rapid activation of Rap1. Treatment of cells with the Ca2+ chelator BAPTA-AM and inhibition of Src and PLD2 with PP2 or 1-butanol, respectively, abrogated P2Y12 receptor-mediated activation of Rap1 and PKB. In addition inhibition of PKCzeta decreased basal and 2MeSADP-stimulated phosphorylation of PKB indicating a role for this PKC isoform in PKB signalling. Although the increased PKB phosphorylation was abolished in the presence of the IGF-I receptor tyrosine kinase inhibitor AG 1024, 2MeSADP did not significantly increase receptor phosphorylation. Nevertheless, phosphorylation of a 120 kDa IGF-I receptor-associated protein was observed. The latter protein was identified by MALDI-TOF/TOF-MS as the proline-rich tyrosine kinase 2 (Pyk2) that co-operates with Src in a PLD2-dependent manner. Consistent with the signalling towards Rap1 and PKB, activation of Pyk2 was abrogated by Ca2+ chelation, inhibition of PLD2 and IGF-I receptor tyrosine kinase activity. In conclusion, the data reveal a novel type of cross-talk between P2Y12 and IGF-I receptors that proceeds through Gbetagamma-, Ca2+-and PLD2-dependent activation of the Pyk2/Src pathway resulting in GTP-loading of Rap1 required for an increased PKB phosphorylation.
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Affiliation(s)
- Kristof Van Kolen
- Laboratory of Cellular Biochemistry, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk-Antwerpen, Belgium
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Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M, Venter J, Alpini G. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006; 12:3523-36. [PMID: 16773709 PMCID: PMC4087568 DOI: 10.3748/wjg.v12.i22.3523] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells (cholangiocytes) are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation (BDL), partial hepatectomy, feeding of bile acids, carbon tetrachloride (CCl4) or α-naphthylisothiocyanate (ANIT)] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units (IBDU) and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary epithelium. These models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile ducts. Future studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Division of R&E, Scott and White Memorial Hospital and The Texas A&M University System Health Science Center College of Medicine, MRB, 702 South West H.K. Dodgen Loop, Temple, Texas 76504, USA.
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11
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Integration of P2Y receptor-activated signal transduction pathways in G protein-dependent signalling networks. Purinergic Signal 2006; 2:451-69. [PMID: 18404483 PMCID: PMC2254474 DOI: 10.1007/s11302-006-9008-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2005] [Accepted: 03/17/2006] [Indexed: 12/21/2022] Open
Abstract
The role of nucleotides in intracellular energy provision and nucleic acid synthesis has been known for a long time. In the past decade, evidence has been presented that, in addition to these functions, nucleotides are also autocrine and paracrine messenger molecules that initiate and regulate a large number of biological processes. The actions of extracellular nucleotides are mediated by ionotropic P2X and metabotropic P2Y receptors, while hydrolysis by ecto-enzymes modulates the initial signal. An increasing number of studies have been performed to obtain information on the signal transduction pathways activated by nucleotide receptors. The development of specific and stable purinergic receptor agonists and antagonists with therapeutical potential largely contributed to the identification of receptors responsible for nucleotide-activated pathways. This article reviews the signal transduction pathways activated by P2Y receptors, the involved second messenger systems, GTPases and protein kinases, as well as recent findings concerning P2Y receptor signalling in C6 glioma cells. Besides vertical signal transduction, lateral cross-talks with pathways activated by other G protein-coupled receptors and growth factor receptors are discussed.
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Ruffels J, Griffin M, Dickenson JM. Activation of ERK1/2, JNK and PKB by hydrogen peroxide in human SH-SY5Y neuroblastoma cells: role of ERK1/2 in H2O2-induced cell death. Eur J Pharmacol 2004; 483:163-73. [PMID: 14729104 DOI: 10.1016/j.ejphar.2003.10.032] [Citation(s) in RCA: 152] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Reactive oxygen species including H(2)O(2) activate an array of intracellular signalling cascades that are closely associated with cell death and cell survival pathways. The human neuroblastoma SH-SY5Y cell line is widely used as model cell system for studying neuronal cell death induced by oxidative stress. However, at present very little is known about the signalling pathways activated by H(2)O(2) in SH-SY5Y cells. Therefore, in this study we have investigated the effect of H(2)O(2) on extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (PKB) activation in undifferentiated and differentiated SH-SY5Y cells. H(2)O(2) stimulated time and concentration increases in ERK1/2, JNK and PKB phosphorylation in undifferentiated and differentiated SH-SY5Y cells. No increases in p38 MAPK phosphorylation were observed following H(2)O(2) treatment. The phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin and LY 294002 ((2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) inhibited H(2)O(2)-induced increases in ERK1/2 and PKB phosphorylation. Furthermore, H(2)O(2)-mediated increases in ERK1/2 activation were sensitive to the MAPK kinase 1 (MEK1) inhibitor PD 98059 (2'-amino-3'-methoxyflavone), whereas JNK responses were blocked by the JNK inhibitor SP 600125 (anthra[1-9-cd]pyrazol-6(2H)-one). Treatment of SH-SY5Y cells with H(2)O(2) (1 mM; 16 h) significantly increased the release of lactate dehydrogenase (LDH) into the culture medium indicative of a decrease in cell viability. Pre-treatment with wortmannin, SP 600125 or SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; p38 MAPK inhibitor) had no effect on H(2)O(2)-induced LDH release from undifferentiated or differentiated SH-SY5Y cells. In contrast, PD 98059 and LY 294002 significantly decreased H(2)O(2)-induced cell death in both undifferentiated and differentiated SH-SY5Y cells. In conclusion, we have shown that H(2)O(2) stimulates robust increases in ERK1/2, JNK and PKB in undifferentiated and differentiated SH-SY5Y cells. Furthermore, the data presented clearly suggest that inhibition of the ERK1/2 pathway protects SH-SY5Y cells from H(2)O(2)-induced cell death.
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Affiliation(s)
- James Ruffels
- School of Science, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
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Hornberger TA, Armstrong DD, Koh TJ, Burkholder TJ, Esser KA. Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction. Am J Physiol Cell Physiol 2004; 288:C185-94. [PMID: 15371259 DOI: 10.1152/ajpcell.00207.2004] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C(2)C(12) myotubes to cyclic uniaxial or multiaxial stretch. Both types of stretch induced an increase in extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt) phosphorylation, but only multiaxial stretch induced ribosomal S6 kinase (p70(S6k)) phosphorylation. Further results demonstrated that the signaling events specific to multiaxial stretch (p70(S6k) phosphorylation) were elicited by forces delivered through the elastic culture membrane and were not due to greater surface area deformations or localized regions of large tensile strain. Experiments performed using medium that was conditioned by multiaxial stretched myotubes indicated that a release of paracrine factors was not sufficient for the induction of signaling to p70(S6k). Furthermore, incubation with gadolinium(III) chloride (500 microM), genistein (250 microM), PD-98059 (250 microM), bisindolylmaleimide I (20 microM), or LY-294002 (100 microM ) did not block the multiaxial stretch-induced signaling to p70(S6k). However, disrupting the actin cytoskeleton with cytochalasin D did block the multiaxial signaling to p70(S6k), with no effect on signaling to PKB/Akt. These results demonstrate that specific types of mechanical stretch activate distinct signaling pathways, and we propose that this occurs through direct mechanosensory-mechanotransduction mechanisms and not through previously defined growth factor/receptor binding pathways.
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Haga M, Yamashita A, Paszkowiak J, Sumpio BE, Dardik A. Oscillatory shear stress increases smooth muscle cell proliferation and Akt phosphorylation. J Vasc Surg 2003; 37:1277-84. [PMID: 12764276 DOI: 10.1016/s0741-5214(03)00329-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE Hemodynamic forces affect smooth muscle cell (SMC) proliferation and migration both in vitro and in vivo. However, the effects of oscillatory shear stress (SS) on SMC proliferation and signal transduction pathways that control survival are not well described. METHODS Bovine aortic SMC were exposed to arterial levels of oscillatory SS (14 dyne/cm(2)) with an orbital shaker; control cells were exposed to static conditions (0 dyne/cm(2)). Cell number and (3)[H]thymidine incorporation were measured after 1, 3, or 5 days of SS. Activation of the Akt pathway was assessed with the Western blot technique. Specificity of the phosphatidylinositol 3-kinase (PI3K) pathway was determined with the Western blot technique with the inhibitors LY294002 (10 micromol/L) or wortmannin (25 nmol/L). RESULTS Arterial levels of oscillatory SS increased SMC cell number by 20.1 +/- 3.7% and (3)[H]thymidine incorporation by 33.4% +/- 6.8% at 5 days. To identify whether SS increased activity of the SMC survival pathway, Akt activation was measured. SMC exposed to SS demonstrated increased Akt phosphorylation compared with control cells, with maximal phosphorylation at 60 minutes. Both PI3K inhibitors specifically inhibited the increase in Akt phosphorylation in SMC exposed to oscillatory SS. CONCLUSION SMC directly respond to oscillatory SS by increasing DNA synthesis, proliferation, and activation of the PI3K-Akt signal transduction pathway. These results suggest a mechanism of SMC survival and proliferation in response to endothelial-denuding arterial injury.
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Affiliation(s)
- Masae Haga
- Department of Surgery, Section of Vascular Surgery, Yale University School of Medicine, 333 Cedar St, FMB 137, New Haven, CT 06520-8062, USA
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