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

Jarkko Hytönen; Olli Leppänen; Jan Hinrich Braesen; Wolf-Hagen Schunck; Dominik Mueller; Friedrich Jung; Christoph Mrowietz; Martin Jastroch; Michael von Bergwelt-Baildon; Kai Kappert; Arnd Heuser; Jörg-Detlef Drenckhahn; Burkert Pieske; Ludwig Thierfelder; Seppo Ylä-Herttuala; Florian Blaschke

doi:10.1161/ATVBAHA.115.306962

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

Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1534-48. doi: 10.1161/ATVBAHA.115.306962. Epub 2016 Jun 9.

Authors

Jarkko Hytönen¹, Olli Leppänen¹, Jan Hinrich Braesen¹, Wolf-Hagen Schunck¹, Dominik Mueller¹, Friedrich Jung¹, Christoph Mrowietz¹, Martin Jastroch¹, Michael von Bergwelt-Baildon¹, Kai Kappert¹, Arnd Heuser¹, Jörg-Detlef Drenckhahn¹, Burkert Pieske¹, Ludwig Thierfelder¹, Seppo Ylä-Herttuala¹, Florian Blaschke²

Affiliations

¹ 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.).
² 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.

PMID: 27283742
DOI: 10.1161/ATVBAHA.115.306962

Abstract

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.

Keywords: blood platelets; coronary in-stent restenosis; endothelial cells; peroxisome proliferator-activated receptors; vascular smooth muscle cells.

MeSH terms

Angioplasty, Balloon / adverse effects
Angioplasty, Balloon / instrumentation*
Animals
Aorta / drug effects*
Aorta / metabolism
Aorta / pathology
Aortic Diseases / metabolism
Aortic Diseases / pathology
Aortic Diseases / prevention & control*
Atherosclerosis / metabolism
Atherosclerosis / pathology
Atherosclerosis / prevention & control*
Blood Platelets / drug effects
Blood Platelets / metabolism
Cardiovascular Agents / administration & dosage*
Carotid Artery Injuries / metabolism
Carotid Artery Injuries / pathology
Cell Movement / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Coronary Artery Disease / metabolism
Coronary Artery Disease / pathology
Coronary Artery Disease / therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Drug-Eluting Stents*
Energy Metabolism / drug effects
Glucose Transporter Type 1 / genetics
Glucose Transporter Type 1 / metabolism
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Mice, Knockout
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
Neointima
PPAR delta / agonists*
PPAR delta / deficiency
PPAR delta / genetics
PPAR delta / metabolism
Platelet Activation / drug effects
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Rats
Rats, Sprague-Dawley
Re-Epithelialization / drug effects
Recurrence
Signal Transduction / drug effects
Steroids / administration & dosage*
Thrombosis / etiology
Thrombosis / metabolism
Thrombosis / pathology
Thrombosis / prevention & control*
Time Factors
Transfection

Substances

Cardiovascular Agents
GW 707
Glucose Transporter Type 1
PDK4 protein, human
PPAR delta
Pdk4 protein, mouse
Pdk4 protein, rat
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Slc2a1 protein, rat
Steroids
Protein Serine-Threonine Kinases