title: Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-beta1-induced CTGF expression in keloid fibroblasts.
abstract: A growing body of evidence suggests the involvement of connective tissue growth factor (CTGF) in the development and maintenance of fibrosis and excessive scarring. As the expression of this protein requires an intact actin cytoskeleton, disruption of the cytoskeleton represents an attractive strategy to decrease CTGF expression and, consequently, excessive scarring. The small heat-shock-related protein (HSP20), when phosphorylated by cyclic nucleotide signaling cascades, displaces phospho-cofilin from the 14-3-3 scaffolding protein leading to activation of cofilin as an actin-depolymerizing protein. In the present study, we evaluated the effect of AZX100, a phosphopeptide analogue of HSP20, on transforming growth factor-beta-1 (TGF-beta1)-induced CTGF and collagen expression in human keloid fibroblasts. We also examined the effect of AZX100 on scar formation in vivo in dermal wounds in a Siberian hamster model. AZX100 decreased the expression of CTGF and type I collagen induced by TGF-beta1, endothelin, and lysophosphatidic acid. Treatment with AZX100 decreased stress fiber formation and altered the morphology of human dermal keloid fibroblasts. In vivo, AZX100 significantly improved collagen organization in a Siberian hamster scarring model. Taken together, these results suggest the potential use of AZX100 as a strategy to prevent excessive scarring and fibrotic disorders.
authors.affiliation: Center for Metabolic Biology, College of Liberal Arts and Sciences, Arizona State University, Tempe, Arizona, USA.
authors.forename: Luciana B
authors.initials: LB
authors.lastname: Lopes
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Furnish
authors.forename: Padmini
authors.initials: P
authors.lastname: Komalavilas
authors.forename: Charles R
authors.initials: CR
authors.lastname: Flynn
authors.forename: Patricia
authors.initials: P
authors.lastname: Ashby
authors.forename: Adam
authors.initials: A
authors.lastname: Hansen
authors.forename: Daphne P
authors.initials: DP
authors.lastname: Ly
authors.forename: George P
authors.initials: GP
authors.lastname: Yang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.forename: Alyssa
authors.initials: A
authors.lastname: Panitch
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brophy
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000378:metabolism; D006224:Cricetinae; D016232:Endothelins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism*; D050888:Heat-Shock Proteins, Small / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007627:Keloid / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D017111:Phodopus; D010750:Phosphoproteins / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C539010:AZX 100; D024042:Collagen Type I; D016232:Endothelins; D050886:HSP20 Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D008246:Lysophospholipids; D010750:Phosphoproteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C032881:lysophosphatidic acid
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