A key role for matrix metalloproteinases and neutral sphingomyelinase-2 in transplant vasculopathy triggered by anti-HLA antibody
| Autor: | Anne Nègre-Salvayre, Magali Trayssac, Jean-Claude Thiers, Lionel Rostaing, Sylvain Galvani, Nassim Kamar, Hans-Willi Krell, Robert Salvayre, Mogens Thomsen, Federico Sallusto, Denis Calise, Nathalie Augé |
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| Přispěvatelé: | Service de biochimie, PRES Université de Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Roche Diagnostics GmbH, Service de néphrologie, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Simon, Marie Francoise, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Néphrologie, dialyse et transplantation [Hôpital de Rangueil, Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Matrix metalloproteinase inhibitor
[SDV]Life Sciences [q-bio] MESH: Piperazines MESH: Antibodies Anti-Idiotypic Constriction Pathologic Mice SCID Matrix metalloproteinase Muscle Smooth Vascular Piperazines Organ transplantation Mice MESH: Matrix Metalloproteinase 14 0302 clinical medicine HLA Antigens MESH: Neointima MESH: RNA Small Interfering MESH: Animals RNA Small Interfering MESH: Mice SCID MESH: HLA Antigens Cells Cultured ComputingMilieux_MISCELLANEOUS [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 0303 health sciences Aniline Compounds biology Arteries MESH: Muscle Smooth Vascular [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Antibodies Anti-Idiotypic 3. Good health Sphingomyelin Phosphodiesterase MESH: Models Animal Models Animal MESH: Vascular Diseases Matrix Metalloproteinase 2 Antibody Cardiology and Cardiovascular Medicine Sphingomyelin MESH: Cells Cultured medicine.medical_specialty Anti-HLA antibody In Vitro Techniques Matrix Metalloproteinase Inhibitors Benzylidene Compounds MESH: Aniline Compounds 03 medical and health sciences Immune system MESH: Constriction Pathologic Neointima Physiology (medical) MESH: Vascular Grafting Matrix Metalloproteinase 14 medicine Animals Humans Vascular Diseases MESH: Mice MESH: Arteries 030304 developmental biology Immunosuppressive treatment Hyperplasia MESH: Humans MESH: Hyperplasia business.industry MESH: Matrix Metalloproteinase 2 Disease Models Animal Pyrimidines MESH: Sphingomyelin Phosphodiesterase MESH: Pyrimidines Immunology biology.protein Vascular Grafting MESH: Benzylidene Compounds MESH: Disease Models Animal business [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology 030215 immunology |
| Zdroj: | Circulation Circulation, American Heart Association, 2011, 124 (24), pp.2725-34. ⟨10.1161/CIRCULATIONAHA.111.021790⟩ Circulation, 2011, 124 (24), pp.2725-34. ⟨10.1161/CIRCULATIONAHA.111.021790⟩ Circulation, American Heart Association, 2011, 124 (24), pp.2725-2734. ⟨10.1161/CIRCULATIONAHA.111.021790⟩ |
| ISSN: | 0009-7322 1524-4539 |
| Popis: | Background— Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy. Methods and Results— Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling mechanism implicating matrix metalloproteinases (MMPs) (membrane type 1 MMP and MMP2) and neutral sphingomyelinase-2. This mitogenic signaling and subsequent DNA synthesis are blocked in smooth muscle cells silenced for MMP2 or for neutral sphingomyelinase-2 by small interfering RNAs, in smooth muscle cells transfected with a vector coding for a dominant-negative form of membrane type 1 MMP, and after treatment by pharmacological inhibitors of MMPs (Ro28-2653) or neutral sphingomyelinase-2 (GW4869). In vivo, Ro28-2653 and GW4869 reduced the intimal thickening induced by anti-HLA antibodies in human mesenteric arteries grafted into severe combined immunodeficiency/beige mice. Conclusions— These data highlight a crucial role for MMP2 and neutral sphingomyelinase-2 in vasculopathy triggered by a humoral immune response and open new perspectives for preventing transplant vasculopathy with the use of MMP and neutral sphingomyelinase inhibitors, in addition to conventional immunosuppression. |
| Databáze: | OpenAIRE |
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