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The NH₂-terminal peptide of –smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo

Department of Pathology, Centre Médical Universitaire, University of Geneva, 1211 Geneva 4, Switzerland

Address correspondence to Giulio Gabbiani, Dept. of Pathology, CMU, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel.: 41-22-702-5742. Fax: 41-22-702-5746. E-mail: Giulio.Gabbiani{at}medecine.unige.ch

Myofibroblasts are specialized fibroblasts responsible for granulation tissue contraction and the soft tissue retractions occurring during fibrocontractive diseases. The marker of fibroblast-myofibroblast modulation is the neo expression of –smooth muscle actin (-SMA), the actin isoform typical of vascular smooth muscle cells that has been suggested to play an important role in myofibroblast force generation. Actin isoforms differ slightly in their NH₂-terminal sequences; these conserved differences suggest different functions. When the NH₂-terminal sequence of -SMA Ac-EEED is delivered to cultured myofibroblast in the form of a fusion peptide (FP) with a cell penetrating sequence, it inhibits their contractile activity; moreover, upon topical administration in vivo it inhibits the contraction of rat wound granulation tissue. The NH₂-terminal peptide of –skeletal actin has no effect on myofibroblasts, whereas the NH₂-terminal peptide of ß–cytoplasmic actin abolishes the immunofluorescence staining for this isoform without influencing -SMA distribution and cell contraction. The FPs represent a new tool to better understand the specific functions of actin isoforms. Our findings support the crucial role of -SMA in wound contraction. The -SMA–FP will be useful for the understanding of the mechanisms of connective tissue remodeling; moreover, it furnishes the basis for a cytoskeleton-dependent preventive and/or therapeutic strategy for fibrocontractive pathological situations.

Key Words: actin isoforms; wound healing; granulation tissue; TGFß; fibrosis

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