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Role of Heat Shock Proteins in Modulating ECM Deposition
Author(s) -
Leavitt Jeffrey,
Whalen Rachel,
Veraldi Kristen,
Binder Robert,
Yates Cecelia
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.925.1
Subject(s) - fibronectin , myofibroblast , extracellular matrix , microbiology and biotechnology , heat shock protein , hsp90 , transforming growth factor , fibroblast , hsp70 , fibrosis , chemistry , transforming growth factor beta , cancer research , biology , pathology , biochemistry , medicine , gene , in vitro
Objective The hallmark feature of systemic sclerosis (SSc) is excessive accumulation of extracellular matrix (ECM) in skin and other affected organs that leads to fibrosis. The accumulation of ECM is caused by pathologically activated fibroblast that releases collagen, fibronectin, and other ECM components. Strong evidence suggests transforming growth factor beta (TGF‐β) plays a pivotal role in fibroblast activation and induces excessive ECM production. In addition, heat shock protein (HSPs) have been implicated in SSc such that pharmacological inhibition of hsp90 blocks the pro‐fibrotic effect of TGF‐β. In this study we evaluate the role of hsp90 and hsp70 on TGF‐β signaling and ECM production in human dermal fibroblasts. Method Expression of hsp90 and hsp70 were quantified by immunoblot and immunofluorescence microscopy following TGF‐β induction of dermal fibroblasts. The effect of hsp90 and hsp70 inhibition on TGF‐β‐induced ECM expression was analyzed in dermal fibroblasts. Results Expression of hsp90 and hsp70 increased in a TGF‐β‐ dependent manner 48 hours after treatments following a marginal, proteasomal‐dependent decrease at 24 hours. Inhibition of hsp90 by 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG) blocked the effects of TGF‐β on fibronectin and alpha‐smooth muscle actin and myofibroblast differentiation. In turn, there was an increase in antifibrotic matrix decorin. Conclusion Our data suggest a critical role for hsp90 in TGF‐β signaling. We propose the use of hsp90 inhibitors as potential antifibrotic treatments. Our data suggest a critical role for hsp90 and hsp70 in TGF‐β signaling. Blockade of TGF‐β‐mediated myofibroblast differentiation by 17‐AAG suggests that hsp90 inhibitors merit additional study as novel antifibrotic agents.