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Chris Smoke ASCB 2009

AZX100 Modulates Actin Dynamics in Hypertrophic and Keloid Myofibroblasts

Christopher C Smoke, Tyler Frye, Kim Perkins, Emma Rousseau, Michael Sheller

Keloid and hypertrophic scar-derived myofibroblasts are characterized by increased stress fibers and contractile function as compared to fibroblasts. This is demonstrated as an increased ratio of filamentous (F) actin to globular (G) actin.  Previous research suggests that AZX100, a 24 amino acid phosphopeptide analogue of Heat Shock Protein Beta 6 (HSPB6 or HSP20) containing a protein transduction domain, binds to 14-3-3, displacing phospho-cofilin and increasing cofilin-dependent depolymerization of actin, resulting in an increased pool of G-actin.

The present study investigated the ability of AZX100 to reduce the F-actin content of dermal myofibroblasts.  Experimentally, keloid and hypertrophic scar-derived fibroblasts were serum starved for 24 hours, followed by treatment with Transforming Growth Factor Beta 1 (TGFβ1) at 2.5ng/ml alone or in the presence of 25mM AZX100 for 24 hours.  F-actin was then separated from G-actin by ultra centrifugation techniques and the amounts of each were determined by Western blot analysis.  AZX100 treatment of hypertrophic and keloid derived myofibroblasts decreased the pool of F-actin by 20% and 16%, respectively.  AZX100 treatment of keloid and hypertrophic myofibroblasts visually reduced stress fiber formation as measured by immunofluorescence.  Additionally, treatment of fibroblasts with AZX100 in the presence of TGFb1 reduced the amount of a smooth muscle actin mRNA compared to fibroblasts treated with TGFb1 alone.  The data suggest that AZX100 disrupts the cytoskeleton network in persistent myofibroblasts and improves healing by decreasing fibrotic scar formation.

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