title: TGFβ1 regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism.
abstract: In cardiac wound healing following myocardial infarction (MI), relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that produce large quantities of extracellular matrix (ECM) and fibrillar collagen proteins. Our laboratory and others have identified TGFβ1 as being a persistent stimulus in the chronic and inappropriate wound healing phase that is marked by hypertrophic scarring and eventual stiffening of the entire myocardium, ultimately leading to the pathogenesis of heart failure following MI. Ski is a potent negative regulator of TGFβ/Smad signaling with known antifibrotic effects. Conversely, Scleraxis is a potent profibrotic basic helix-loop-helix transcription factor that stimulates fibrillar collagen expression. We hypothesize that TGFβ1 induces Scleraxis expression by a novel Smad-independent pathway. Our data support the hypothesis that Scleraxis expression is induced by TGFβ1 through a Smad-independent pathway in the cardiac myofibroblast. Specifically, we demonstrate that TGFβ1 stimulates p42/44 (Erk1/2) kinases, which leads to increased Scleraxis expression. Inhibition of MEK1/2 using U0126 led to a sequential temporal reduction of phospho-p42/44 and subsequent Scleraxis expression. We also found that adenoviral Ski expression in primary myofibroblasts caused a significant repression of endogenous Scleraxis expression at both the mRNA and protein levels. Thus we have identified a novel TGFβ1-driven, Smad-independent, signaling cascade that may play an important role in regulating the fibrotic response in activated cardiac myofibroblasts following cardiac injury.
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Zeglinski
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Patricia
authors.initials: P
authors.lastname: Roche
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Mark
authors.initials: M
authors.lastname: Hnatowich
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Internal Medicine, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
authors.affiliation: Department of Biochemistry and Medical Genetics, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Wigle
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czubryt
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; idixon@sbrc.ca.
authors.forename: Ian M C
authors.initials: IM
authors.lastname: Dixon
mesh_terms: D016475:3T3 Cells; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002070:Butadienes / Q000494:pharmacology; D019556:COS Cells; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D005355:Fibrosis / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002070:Butadienes; D019950:Mitogen-Activated Protein Kinase 1; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C503819:Scx protein, rat; C525545:Ski protein, rat; C508962:Tgfb1 protein, rat; C113580:U 0126
keywords: MAPK; Scleraxis; Ski; TGFβ; myofibroblast