Activation of Peroxisome Proliferator–Activated Receptor-δ as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis
| Autor: | Wolf-Hagen Schunck, Michael von Bergwelt-Baildon, Martin Jastroch, Florian Blaschke, Jarkko P. Hytönen, Seppo Ylä-Herttuala, Burkert Pieske, Olli Leppänen, C. Mrowietz, Jörg-Detlef Drenckhahn, Ludwig Thierfelder, Kai Kappert, Friedrich Jung, Jan Hinrich Braesen, Dominik N Mueller, Arnd Heuser |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Time Factors medicine.medical_treatment Coronary Artery Disease 030204 cardiovascular system & hematology GW0742 Muscle Smooth Vascular Rats Sprague-Dawley 0302 clinical medicine Re-Epithelialization Restenosis Cell Movement Recurrence PPAR delta Aorta Cells Cultured Mice Knockout Glucose Transporter Type 1 Drug-Eluting Stents Cardiology Steroids Peroxisome proliferator-activated receptor delta Technology Platforms Cardiology and Cardiovascular Medicine Signal Transduction Blood Platelets Neointima medicine.medical_specialty Myocytes Smooth Muscle Aortic Diseases Protein Serine-Threonine Kinases Transfection 03 medical and health sciences Coronary Restenosis Peroxisome Proliferator-activated Receptors Stents Internal medicine Thrombocyte activation Human Umbilical Vein Endothelial Cells medicine Animals Humans Platelet activation Cell Proliferation Dose-Response Relationship Drug business.industry Pyruvate Dehydrogenase Acetyl-Transferring Kinase Stent Cardiovascular Agents Thrombosis Atherosclerosis Platelet Activation medicine.disease Rats Disease Models Animal 030104 developmental biology Cardiovascular and Metabolic Diseases Cardiovascular agent Cancer research Carotid Artery Injuries Energy Metabolism business Angioplasty Balloon |
| Zdroj: | Arterioscler. Thromb. Vasc. Biol. 36, 1534-1548 (2016) |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.115.306962 |
| Popis: | Objective— Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator–activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement. Approach and Results— Here, we report that PPARδ ligand–coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor–stimulated proliferation and migration. Conclusions— In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes. |
| Databáze: | OpenAIRE |
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