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.

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