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Peroxisome proliferator-activated receptor- abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator

Asish K. Ghosh^*,1, Swati Bhattacharyya, Jun Wei, Suyeon Kim, Yaacov Barak, Yasuji Mori and John Varga^,1

^* Feinberg Cardiovascular Research Institute and

Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; and

The Jackson Laboratory, Bar Harbor, Maine, USA

¹ Correspondence: A.K.G., Feinberg Cardiovascular Research Institute, 303 E. Chicago Ave., Chicago, IL 60611, USA. E-mail: a-ghosh2{at}northwestern.edu; J.V., Division of Rheumatology, Northwestern University Feinberg School of Medicine, M300 McGaw Pavillion, 240 E. Huron St., Chicago, IL 60611 USA. E-mail: j-varga{at}northwestern.edu

Ligands of peroxisome proliferator-activated receptor- (PPAR-) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-β). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR- in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-β activity by PPAR- ligands involves cellular PPAR-, since 15-deoxy-12,14-prostaglandin J₂ (15d-PGJ₂) failed to block TGF-β-induced responses in either primary cultures of PPAR--null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-. Next, we examined the molecular basis underlying the abrogation of TGF-β signaling by PPAR- in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR- without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-β, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-β-induced stimulation of COL1A2 in the presence of PPAR- ligands. Collectively, these results indicate that PPAR- blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-β-induced collagen gene expression. Pharmacological activation of PPAR- thus may represent a novel therapeutic approach to target p300-dependent TGF-β profibrotic responses such as stimulation of collagen gene expression.—Ghosh, A. K., Bhattacharyya, S., Wei, J., Kim, S., Barak, Y., Mori, Y., and Varga, J. Peroxisome proliferator-activated receptor- abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

Key Words: fibrosis • 15d-PGJ₂ • type I collagen • fibroblast • acetyltransferase

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