title: Role of scleraxis in mechanical stretch-mediated regulation of cardiac myofibroblast phenotype.
abstract: The phenotype conversion of fibroblasts to myofibroblasts plays a key role in the pathogenesis of cardiac fibrosis. Numerous triggers of this conversion process have been identified, including plating of cells on solid substrates, cytokines such as transforming growth factor-β, and mechanical stretch; however, the underlying mechanisms remain incompletely defined. Recent studies from our laboratory revealed that the transcription factor scleraxis is a key regulator of cardiac fibroblast phenotype and extracellular matrix expression. Here we report that mechanical stretch induces type I collagen expression and morphological changes indicative of cardiac myofibroblast conversion, as well as scleraxis expression via activation of the scleraxis promoter. Scleraxis causes phenotypic changes similar to stretch, and the effect of stretch is attenuated in scleraxis null cells. Scleraxis was also sufficient to upregulate expression of vinculin and F-actin, to induce stress fiber and focal adhesion formation, and to attenuate both cell migration and proliferation, further evidence of scleraxis-mediated regulation of fibroblast to myofibroblast conversion. Together, these data confirm that scleraxis is sufficient to promote the myofibroblast phenotype and is a required effector of stretch-mediated conversion. Scleraxis may thus represent a potential target for the development of novel antifibrotic therapies aimed at inhibiting myofibroblast formation.
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Roche
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Raghu S
authors.initials: RS
authors.lastname: Nagalingam
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Rushita A
authors.initials: RA
authors.lastname: Bagchi
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Nina
authors.initials: N
authors.lastname: Aroutiounova
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Breanna M J
authors.initials: BM
authors.lastname: Belisle
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Wigle
authors.affiliation: St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada; and mczubryt@sbrc.ca.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czubryt
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism* / Q000502:physiology*; D041681:NIH 3T3 Cells; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; D024042:Collagen Type I; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
keywords: cardiac fibroblast; migration; proliferation; stretch; transcription factor