title: Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting.
abstract: BACKGROUND
  ε protein kinase C (εPKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of εPKC in the development of restenosis.
  
  
  RESULTS
  Rat models of aortic balloon injury with or without subsequent stenting were used. Rats were treated with the selective ψεPKC activator ε receptor for activated protein kinase C (ψεRACK), the selective εPKC inhibitor εV1-2, or saline. Both down-stream cascades of the platelet-derived growth factor receptor via extracellular signal-regulated kinase and Akt, respectively, were evaluated in vivo and in VSMC cultures. Intimal hyperplasia with luminal obliteration developed in saline-treated balloon-injured rat aortas (20.3±8.0%), and ψεRACK significantly promoted neointima development (32.4±4.9%, P=0.033), whereas εV1-2 significantly inhibited luminal narrowing (9.2±4.3%, P=0.039). εPKC inhibition led to significantly reduced VSMC extracellular signal-regulated kinase phosphorylation in vivo, whereas Akt phosphorylation was not markedly affected. Neointimal proliferation in vivo and platelet-derived growth factor-induced VSMC proliferation/migration in vitro were significantly inhibited by εV1-2. The inhibition of the platelet-derived growth factor pathway was mediated by inhibiting down-stream extracellular signal-regulated kinase and Akt phosphorylation. In vitro, εV1-2 showed inhibitory properties on endothelial cell proliferation, but that did not prevent reendothelialization in vivo. εV1-2 showed proapoptotic effects on VSMC in vitro. After stent implantation, luminal restenosis (quantified by optical coherence tomography imaging) was significantly reduced with εV1-2 (8.0±2.0%) compared with saline (20.2±9.8%, P=0.028).
  
  
  CONCLUSIONS
  εPKC seems to be centrally involved in the development of neointimal hyperplasia. We suggest that εPKC inhibition may be mediated via inhibition of extracellular signal-regulated kinase and Akt activation. εPKC modulation may become a new therapeutic target against vascular restenosis.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Koyanagi
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeno
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000293:injuries; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000201:enzymology; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases