April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Atypical Protein Kinase C (aPCK) Inhibitors Block Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Endothelial Permeability
Author Affiliations & Notes
  • Paul M. Titchenell
    Cellular & Molecular Physiology,
    Pennsylvania State University College of Medicine, Hershey, Pennsylvania
  • Edward A. Felinski
    Cellular & Molecular Physiology,
    Pennsylvania State University College of Medicine, Hershey, Pennsylvania
  • Cheng-Mao Lin
    Kellogg Eye Center University of Michigan, Ann Arbor, Michigan
  • Jeffrey M. Sundstrom
    Ophthalmology,
    Pennsylvania State University College of Medicine, Hershey, Pennsylvania
  • Charles D. Smith
    Pharmaceutical Sciences, University of South Carolina, Charleston, South Carolina
  • David A. Antonetti
    Kellogg Eye Center University of Michigan, Ann Arbor, Michigan
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 4858. doi:
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      Paul M. Titchenell, Edward A. Felinski, Cheng-Mao Lin, Jeffrey M. Sundstrom, Charles D. Smith, David A. Antonetti; Atypical Protein Kinase C (aPCK) Inhibitors Block Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Endothelial Permeability. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4858.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : VEGF contributes to the loss of the blood-retinal barrier and subsequent macular edema in diabetic retinopathy. VEGF signaling requires conventional PKC (PKCβ) activity and leads to phosphorylation and internalization of tight junction proteins and vascular permeability. However, PKCβ inhibition is only partially effective at preventing VEGF-induced vascular permeability suggesting the involvement of alternative signaling pathways. Here, we provide evidence for the involvement of aPKC signaling in VEGF-induced endothelial permeability and identify a novel class of small molecule inhibitors of PKCζ.

Methods: : Over-expression of wild-type and dominant negative PKCζ transgenes were used to assess PKCζ’s contribution to endothelial permeability in culture. Novel aPKC inhibitors were screened from a chemical library and characterized utilizing in vitro kinase assays. Moreover, these compounds were tested for their ability to prevent VEGF-induced permeability in both primary cell culture and in vivo by measuring flux of a 70kDa dextran tracer and Evan’s Blue dye retinal extravasation, respectively. Immuno-labeling was performed to determine organization of tight junction proteins at the cell border after VEGF treatment and in the presence or absence of PKCζ inhibitor.

Results: : Exogenous over-expression of wild-type PKCζ potentiates VEGF-induced permeability while dominant negative expression attenuates the effect. Additionally, novel aPKC inhibitors completely block VEGF-induced permeability in cell culture and animal models while restoring border localization of tight junction proteins.

Conclusions: : These results demonstrate an aPKC signaling requirement for VEGF-induced permeability as was observed for tumor necrosis factor α. The development of aPKC inhibitors may provide a novel therapeutic option to treat vascular permeability in diabetic macular edema.

Keywords: diabetic retinopathy • growth factors/growth factor receptors • drug toxicity/drug effects 
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