Title |
PPAR-γ Ligands Repress TGFβ-Induced Myofibroblast Differentiation by Targeting the PI3K/Akt Pathway: Implications for Therapy of Fibrosis
|
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Published in |
PLOS ONE, January 2011
|
DOI | 10.1371/journal.pone.0015909 |
Pubmed ID | |
Authors |
Ajit A. Kulkarni, Thomas H. Thatcher, Keith C. Olsen, Sanjay B. Maggirwar, Richard P. Phipps, Patricia J. Sime |
Abstract |
Transforming growth factor beta (TGFβ) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFβ signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands inhibit TGFβ-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. TGFβ also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway leading to phosphorylation of Akt(S473). Here, we report that PPAR-γ ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15d-prostaglandin J(2) (15d-PGJ(2)), inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF) fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR-γ-independent mechanism. The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFβ-stimulated myofibroblast differentiation, as determined by Western blotting for α-smooth muscle actin and calponin. Prostaglandin A(1) (PGA(1)), a structural analogue of 15d-PGJ(2) with an electrophilic center, also reduced TGFβ-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2) and CDDO is dependent on their electrophilic properties. PPAR-γ ligands inhibited TGFβ-induced Akt phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFβ-induced phosphorylation of FAK, a kinase that acts upstream of Akt. Thus, PPAR-γ ligands inhibit TGFβ signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of PPAR-γ ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | <1% |
Unknown | 135 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 37 | 27% |
Student > Master | 21 | 15% |
Researcher | 19 | 14% |
Student > Doctoral Student | 12 | 9% |
Professor > Associate Professor | 6 | 4% |
Other | 20 | 15% |
Unknown | 21 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 34 | 25% |
Medicine and Dentistry | 31 | 23% |
Biochemistry, Genetics and Molecular Biology | 31 | 23% |
Pharmacology, Toxicology and Pharmaceutical Science | 7 | 5% |
Immunology and Microbiology | 3 | 2% |
Other | 6 | 4% |
Unknown | 24 | 18% |