Document Detail


Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting.
MedLine Citation:
PMID:  20837910     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Tobias Deuse; Tomoyoshi Koyanagi; Reinhold G Erben; Xiaoqin Hua; Joachim Velden; Fumiaki Ikeno; Hermann Reichenspurner; Robert C Robbins; Daria Mochly-Rosen; Sonja Schrepfer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-14     Completed Date:  2010-10-01     Revised Date:  2014-11-09    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S170-8     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta* / enzymology,  injuries
Apoptosis / drug effects
Cell Movement / drug effects
Cell Proliferation
Cells, Cultured
Coculture Techniques
Endothelial Cells / enzymology*
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism
Graft Occlusion, Vascular* / enzymology
Humans
Male
Myocytes, Smooth Muscle / enzymology*
Phosphorylation / drug effects
Platelet-Derived Growth Factor / metabolism
Protein Kinase C-epsilon* / antagonists & inhibitors,  metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
R01 HL052141/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Platelet-Derived Growth Factor; 0/Protein Kinase Inhibitors; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.13/Protein Kinase C-epsilon; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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