Prostaglandin E2 Inhibits {alpha}-Smooth Muscle Actin Transcription During Myofibroblast Differentiation via Distinct Mechanisms of Modulation of Serum Response Factor and Myocardin-Related Transcription Factor-A [Signal Transduction]

May 5th, 2014 by Penke, L. R. K., Huang, S. K., White, E. S., Peters-Golden, M.

Differentiation of lung fibroblasts into contractile protein-expressing myofibroblasts by transforming growth factor-β1 (TGF-β1) is a critical event in the pathogenesis of pulmonary fibrosis. Transcription of the contractile protein α-smooth muscle actin (α-SMA) is mediated by the transcription factor serum response factor (SRF) along with its coactivator, myocardin-related transcription factor-A (MRTF-A). The endogenous lipid mediator prostaglandin E2 (PGE2) exerts anti-fibrotic effects, including the inhibition of myofibroblast differentiation. However, the mechanism by which PGE2 inhibits α-SMA expression is incompletely understood. Here we show in normal lung fibroblasts that PGE2 reduced the nuclear accumulation of MRTF-A-SRF complexes and consequently inhibited α-SMA promoter activation. It did so both by independently 1) inhibiting SRF gene expression by interrupting p38 activation, and 2) inhibiting nuclear import of MRTF-A via activation of cofilin 1 and inactivation of vasodilator-stimulated phosphoprotein. Similar effects of PGE2 on SRF gene expression were observed in fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis. Thus, PGE2 is the first substance described to prevent myofibroblast differentiation by disrupting - via distinct mechanisms - the actions of both SRF and MRTF-A.
  • Posted in Journal of Biological Chemistry, Publications
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