학술논문
Protein Tyrosine Phosphatase 1B Deficiency in Vascular Smooth Muscle Cells Promotes Perivascular Fibrosis following Arterial Injury.
Document Type
Academic Journal
Author
Gogiraju R; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; Gachkar S; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; Velmeden D; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; Bochenek ML; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.; Zifkos K; Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.; Hubert A; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; Münzel T; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Rhine-Main Site, Mainz, Germany.; Offermanns S; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.; Centre for Molecular Medicine, Medical Faculty, JW Goethe University Frankfurt, Frankfurt, Germany.; Cardiopulmonary Institute (CPI), Frankfurt, Germany.; German Center for Cardiovascular Research (DZHK e.V.), Rhine-Main Site, Frankfurt and Bad Nauheim, Germany.; Schäfer K; Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Rhine-Main Site, Mainz, Germany.
Source
Publisher: Thieme Country of Publication: Germany NLM ID: 7608063 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2567-689X (Electronic) Linking ISSN: 03406245 NLM ISO Abbreviation: Thromb Haemost Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Smooth muscle cell (SMC) phenotype switching plays a central role during vascular remodeling. Growth factor receptors are negatively regulated by protein tyrosine phosphatases (PTPs), including its prototype PTP1B. Here, we examine how reduction of PTP1B in SMCs affects the vascular remodeling response to injury.
Methods: Mice with inducible PTP1B deletion in SMCs (SMC.PTP1B-KO) were generated by crossing mice expressing Cre.ERT2 recombinase under the Myh11 promoter with PTP1B flox/flox mice and subjected to FeCl 3 carotid artery injury.
Results: Genetic deletion of PTP1B in SMCs resulted in adventitia enlargement, perivascular SMA+ and PDGFRβ + myofibroblast expansion, and collagen accumulation following vascular injury. Lineage tracing confirmed the appearance of Myh11 -Cre reporter cells in the remodeling adventitia, and SCA1 + CD45 - vascular progenitor cells increased. Elevated mRNA expression of transforming growth factor β (TGFβ) signaling components or enzymes involved in extracellular matrix remodeling and TGFβ liberation was seen in injured SMC.PTP1B-KO mouse carotid arteries, and mRNA transcript levels of contractile SMC marker genes were reduced already at baseline. Mechanistically, Cre recombinase (mice) or siRNA (cells)-mediated downregulation of PTP1B or inhibition of ERK1/2 signaling in SMCs resulted in nuclear accumulation of KLF4, a central transcriptional repressor of SMC differentiation, whereas phosphorylation and nuclear translocation of SMAD2 and SMAD3 were reduced. SMAD2 siRNA transfection increased protein levels of PDGFRβ and MYH10 while reducing ERK1/2 phosphorylation, thus phenocopying genetic PTP1B deletion.
Conclusion: Chronic reduction of PTP1B in SMCs promotes dedifferentiation, perivascular fibrosis, and adverse remodeling following vascular injury by mechanisms involving an ERK1/2 phosphorylation-driven shift from SMAD2 to KLF4-regulated gene transcription.
Competing Interests: None declared.
(The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
Methods: Mice with inducible PTP1B deletion in SMCs (SMC.PTP1B-KO) were generated by crossing mice expressing Cre.ER
Results: Genetic deletion of PTP1B in SMCs resulted in adventitia enlargement, perivascular SMA
Conclusion: Chronic reduction of PTP1B in SMCs promotes dedifferentiation, perivascular fibrosis, and adverse remodeling following vascular injury by mechanisms involving an ERK1/2 phosphorylation-driven shift from SMAD2 to KLF4-regulated gene transcription.
Competing Interests: None declared.
(The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)