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Vascular Biology

Loss of β-Catenin Promotes Chondrogenic Differentiation of Aortic Valve Interstitial Cells

Ming Fang, Christina M. Alfieri, Alexia Hulin, Simon J. Conway, Katherine E. Yutzey
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https://doi.org/10.1161/ATVBAHA.114.304579
Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304579
Originally published October 23, 2014
Ming Fang
From the Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.J.C.).
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Christina M. Alfieri
From the Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.J.C.).
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Alexia Hulin
From the Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.J.C.).
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Simon J. Conway
From the Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.J.C.).
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Katherine E. Yutzey
From the Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (S.J.C.).
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Abstract

Objective—The Wnt/β-catenin signaling pathway has been implicated in human heart valve disease and is required for early heart valve formation in mouse and zebrafish. However, the specific functions of Wnt/β-catenin signaling activity in heart valve maturation and maintenance in adults have not been determined previously.

Approach and Results—Here, we show that Wnt/β-catenin signaling inhibits Sox9 nuclear localization and proteoglycan expression in cultured chicken embryo aortic valves. Loss of β-catenin in vivo in mice, using Periostin(Postn)Cre–mediated tissue-restricted loss of β-catenin (Ctnnb1) in valvular interstitial cells, leads to the formation of aberrant chondrogenic nodules and induction of chondrogenic gene expression in adult aortic valves. These nodular cells strongly express nuclear Sox9, and Sox9 downstream chondrogenic extracellular matrix genes, including Aggrecan, Col2a1, and Col10a1. Excessive chondrogenic proteoglycan accumulation and disruption of stratified extracellular matrix maintenance in the aortic valve leaflets are characteristics of myxomatous valve disease. Both in vitro and in vivo data demonstrate that the loss of Wnt/β-catenin signaling leads to increased nuclear expression of Sox9 concomitant with induced expression of chondrogenic extracellular matrix proteins.

Conclusions—β-Catenin limits Sox9 nuclear localization and inhibits chondrogenic differentiation during valve development and in adult aortic valve homeostasis.

  • aortic valve
  • chondrogenesis
  • proteoglycans
  • Received September 3, 2014.
  • Accepted October 14, 2014.
  • © 2014 American Heart Association, Inc.
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    Loss of β-Catenin Promotes Chondrogenic Differentiation of Aortic Valve Interstitial Cells
    Ming Fang, Christina M. Alfieri, Alexia Hulin, Simon J. Conway and Katherine E. Yutzey
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304579, originally published October 23, 2014
    https://doi.org/10.1161/ATVBAHA.114.304579

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    Loss of β-Catenin Promotes Chondrogenic Differentiation of Aortic Valve Interstitial Cells
    Ming Fang, Christina M. Alfieri, Alexia Hulin, Simon J. Conway and Katherine E. Yutzey
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.304579, originally published October 23, 2014
    https://doi.org/10.1161/ATVBAHA.114.304579
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