PLD1 promotes reactive oxygen species production in vascular smooth muscle cells and injury-induced neointima formation |
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| Institution: | 1. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;2. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China;3. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA;4. Biochemistry and Cell Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA;1. Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA 02118, USA;2. Endocrinology Department of the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;3. CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Spain;4. Cardiovascular Biochemistry Group, Research Institute of the Hospital de Sant Pau, CIBERDEM, Barcelona, Spain;1. Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy;2. INBB, National Institute for Biostructures and Biosystems, Viale delle Medaglie d''Oro 305, 00136 Rome, Italy;3. Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden;4. Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy;5. National Cancer Research Center, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy;1. Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;2. Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;3. Project Management Department, Shionogi & Co., Ltd, 8F (Reception) / 9F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan;4. Research Planning Department, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;1. Laboratory of Biochemistry, Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece;2. Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, Agia Paraskevi, Athens, Greece;1. Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany;2. Institute of Biochemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;3. Department of Microbiology and Biotechnology, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany;4. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;5. Centro de Bioinformática y Simulación Molecular (CBSM), Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, CL-3460000 Talca, Chile;6. Synthetic Membrane Systems, Institute of Biochemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;7. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany;8. Institute of Bio- and Geosciences, Plant Sciences (IBG-2) and Agrosphere (IBG-3), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany |
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| Abstract: | Phospholipase D (PLD) generates the signaling lipid phosphatidic acid (PA) and has been known to mediate proliferation signal in vascular smooth muscle cells (VSMCs). However, it remains unclear how PLD contributes to vascular diseases. VSMC proliferation directly contributes to the development and progression of cardiovascular disease, such as atherosclerosis and restenosis after angioplasty. Using the mouse carotid artery ligation model, we find that deletion of Pld1 gene inhibits neointima formation of the injuried blood vessels. PLD1 deficiency reduces the proliferation of VSMCs in both injured artery and primary cultures through the inhibition of ERK1/2 and AKT signals. Immunohistochemical staining of injured artery and flow cytometry analysis of VSMCs shows a reduction of the levels of reactive oxygen species (ROS) in Pld1?/? VSMCs. An increase of intracellular ROS by hydrogen peroxide stimulation restored the reduced activities of ERK and AKT in Pld1?/? VSMCs, whereas a reduction of ROS by N-acetyl-l-cysteine (NAC) scavenger lowered their activity in wild-type VSMCs. These results indicate that PLD1 plays a critical role in neointima, and that PLD1 mediates VSMC proliferation signal through promoting the production of ROS. Therefore, inhibition of PLD1 may be used as a therapeutic approach to suppress neointimal formation in atherosclerosis and restenosis after angioplasty. |
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