title: Tgfβ-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves.
abstract: Mature heart valves are complex structures consisting of three highly organized extracellular matrix layers primarily composed of collagens, proteoglycans and elastin. Collectively, these diverse matrix components provide all the necessary biomechanical properties for valve function throughout life. In contrast to healthy valves, myxomatous valve disease is the most common cause of mitral valve prolapse in the human population and is characterized by an abnormal abundance of proteoglycans within the valve tri-laminar structure. Despite the clinical significance, the etiology of this phenotype is not known. Scleraxis (Scx) is a basic-helix-loop-helix transcription factor that we previously showed to be required for establishing heart valve structure during remodeling stages of valvulogenesis. In this study, we report that remodeling heart valves from Scx null mice express decreased levels of proteoglycans, particularly chondroitin sulfate proteoglycans (CSPGs), while overexpression in embryonic avian valve precursor cells and adult porcine valve interstitial cells increases CSPGs. Using these systems we further identify that Scx is positively regulated by canonical Tgfβ2 signaling during this process and this is attenuated by MAPK activity. Finally, we show that Scx is increased in myxomatous valves from human patients and mouse models, and overexpression in human mitral valve interstitial cells modestly increases proteoglycan expression consistent with myxomatous mitral valve phenotypes. Together, these studies identify an important role for Scx in regulating proteoglycans in embryonic and mature valve cells and suggest that imbalanced regulation could influence myxomatous pathogenesis.
authors.affiliation: Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, P.O. Box 016189 (R-189), Miami, FL, USA; Center for Cardiovascular and Pulmonary Research at Nationwide Children's Hospital Research Institute, 700 Children's Drive, Columbus, OH 43205, USA; The Heart Center at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Damien N
authors.initials: DN
authors.lastname: Barnette
authors.forename: Alexia
authors.initials: A
authors.lastname: Hulin
authors.forename: A S Ishtiaq
authors.initials: AS
authors.lastname: Ahmed
authors.forename: Alain C
authors.initials: AC
authors.lastname: Colige
authors.forename: Mohamad
authors.initials: M
authors.lastname: Azhar
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002645:Chickens; D004195:Disease Models, Animal; D006351:Heart Valves / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008943:Mitral Valve / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D011509:Proteoglycans / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism*; D034421:Sus scrofa; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D011509:Proteoglycans; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Heart valve; MAPK; Myxomatous; Proteoglycan; Scleraxis; Tgfβ