Activation of Peroxisome Proliferator-Activated Receptor-δ as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis.
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.



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.



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.
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Jarkko
J
Hytönen
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Olli
O
Leppänen
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Jan Hinrich
JH
Braesen
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Wolf-Hagen
WH
Schunck
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Dominik
D
Mueller
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Friedrich
F
Jung
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Christoph
C
Mrowietz
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Martin
M
Jastroch
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Michael
M
von Bergwelt-Baildon
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Kai
K
Kappert
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Arnd
A
Heuser
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Jörg-Detlef
JD
Drenckhahn
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Burkert
B
Pieske
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Ludwig
L
Thierfelder
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.).
Seppo
S
Ylä-Herttuala
From the Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (J.H., S.Y.-H.); Centre for R&D, Uppsala University/County Council of Gaevleborg, Gaevle, Sweden (O.L.); Institute for Pathology, University Clinic of Schleswig-Holstein, Campus Kiel, Kiel, Germany (J.H.B.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., D.M., A.H., J.-D.D., L.T., F.B.); Department of Cardiology (B.P., F.B.) and Center for Cardiovascular Research/CCR, Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry (K.K.), Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz-Zentrum Geesthacht, Teltow, Germany (F.J., C.M.); Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, Munich, German Research Center for Environmental Health, Germany (M.J.); and Cologne Interventional Immunology, University Hospital of Cologne, Cologne, Germany (M.v.B.-B.). florian.blaschke@charite.de.
Florian
F
Blaschke
D000800:Angioplasty, Balloon / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D004734:Energy Metabolism / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D047494:PPAR delta / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D062326:Re-Epithelialization / Q000187:drug effects; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000008:administration & dosage*; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014162:Transfection
D002317:Cardiovascular Agents; C442817:GW 707; D051272:Glucose Transporter Type 1; C000631432:PDK4 protein, human; D047494:PPAR delta; C000631439:Pdk4 protein, mouse; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495679:Slc2a1 protein, rat; D013256:Steroids; D017346:Protein Serine-Threonine Kinases
blood platelets; coronary in-stent restenosis; endothelial cells; peroxisome proliferator-activated receptors; vascular smooth muscle cells