Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation invitro

A potentially novel therapy for corneal scarring

Ajay Kuriyan, G. M. Lehmann, A. A. Kulkarni, C. F. Woeller, S. E. Feldon, H. B. Hindman, P. J. Sime, K. R. Huxlin, R. P. Phipps

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A critical component of corneal scarring is the TGFβ-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In thisstudy, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-Δ -12,14-prostaglandin J 2 (15d-PGJ 2) for inhibiting TGFβ-induced myofibroblast differentiation invitro. TGFβ was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ 2 were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFβ-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ 2) potently inhibited TGFβ-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ 2 are strong inhibitors of TGFβ-induced corneal fibroblast to myofibroblast differentiation invitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.

Original languageEnglish (US)
Pages (from-to)136-145
Number of pages10
JournalExperimental Eye Research
Volume94
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Myofibroblasts
PPAR gamma
Cicatrix
Fibroblasts
Ligands
Prostaglandins
Esters
Therapeutics
Acids
Corneal Keratocytes
Collagen
Fibronectins
Fluorescent Antibody Technique
Animal Models
Western Blotting
Messenger RNA

Keywords

  • Corneal scarring
  • Myofibroblast differentiation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation invitro : A potentially novel therapy for corneal scarring. / Kuriyan, Ajay; Lehmann, G. M.; Kulkarni, A. A.; Woeller, C. F.; Feldon, S. E.; Hindman, H. B.; Sime, P. J.; Huxlin, K. R.; Phipps, R. P.

In: Experimental Eye Research, Vol. 94, No. 1, 01.2012, p. 136-145.

Research output: Contribution to journalArticle

Kuriyan, A, Lehmann, GM, Kulkarni, AA, Woeller, CF, Feldon, SE, Hindman, HB, Sime, PJ, Huxlin, KR & Phipps, RP 2012, 'Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation invitro: A potentially novel therapy for corneal scarring', Experimental Eye Research, vol. 94, no. 1, pp. 136-145. https://doi.org/10.1016/j.exer.2011.11.018
Kuriyan, Ajay ; Lehmann, G. M. ; Kulkarni, A. A. ; Woeller, C. F. ; Feldon, S. E. ; Hindman, H. B. ; Sime, P. J. ; Huxlin, K. R. ; Phipps, R. P. / Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation invitro : A potentially novel therapy for corneal scarring. In: Experimental Eye Research. 2012 ; Vol. 94, No. 1. pp. 136-145.
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