M Victoria Gomez-Stallons1, Elaine E Wirrig-Schwendeman1, Keira R Hassel1, Simon J Conway1, Katherine E Yutzey2. 1. From the Heart Institute, Cincinnati Children's Hospital Medical Center, OH (M.V.G.-S., E.E.W.-S., K.R.H., K.E.Y.); Department of Pediatrics, College of Medicine, University of Cincinnati, OH (M.V.G.-S., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN (S.J.C.). 2. From the Heart Institute, Cincinnati Children's Hospital Medical Center, OH (M.V.G.-S., E.E.W.-S., K.R.H., K.E.Y.); Department of Pediatrics, College of Medicine, University of Cincinnati, OH (M.V.G.-S., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN (S.J.C.). Katherine.Yutzey@cchmc.org.
Abstract
OBJECTIVE: Calcific aortic valve disease (CAVD) is the most prevalent type of heart valve disease, affecting ≈2% of the US population. CAVD is characterized by the presence of calcific nodules, resulting in aortic valve (AoV) stenosis; however, the underlying mechanisms driving disease remain unknown. Studies of human diseased AoV provide initial evidence that bone morphogenetic protein (BMP) signaling, essential for normal bone formation, is activated during CAVD. Mice deficient in Klotho, an FGF23 transmembrane coreceptor, exhibit premature aging and develop AoV calcific nodules as occurs in human CAVD. The role of BMP signaling in the development of CAVD was examined in porcine aortic valve interstitial cells (VICs) and Klotho(-/-) mice. APPROACH AND RESULTS: We show that activation of BMP signaling, as indicated by pSmad1/5/8 expression, precedes and later localizes with AoV calcification in Klotho(-/-) mice. In addition, cellular and extracellular matrix changes resembling features of normal bone formation are accompanied by increased osteochondrogenic gene induction in calcified Klotho(-/-) AoV. Likewise, osteogenic media treatment of porcine VICs results in BMP pathway activation, increased osteochondrogenic gene induction, and formation of calcific nodules in vitro. We demonstrate that genetic inactivation of the BMP type IA receptor in Klotho(-/-) aortic VICs, as well as BMP pathway inhibition of osteogenic media-treated aortic VICs in vitro, results in the inhibition of AoV calcification. CONCLUSIONS: BMP signaling and osteochondrogenic gene induction are active in calcified Klotho(-/-) AoV in vivo and calcified porcine aortic VICs in vitro. Importantly, BMP signaling is required for the development of AoV calcification in vitro and in vivo.
OBJECTIVE:Calcific aortic valve disease (CAVD) is the most prevalent type of heart valve disease, affecting ≈2% of the US population. CAVD is characterized by the presence of calcific nodules, resulting in aortic valve (AoV) stenosis; however, the underlying mechanisms driving disease remain unknown. Studies of human diseased AoV provide initial evidence that bone morphogenetic protein (BMP) signaling, essential for normal bone formation, is activated during CAVD. Mice deficient in Klotho, an FGF23 transmembrane coreceptor, exhibit premature aging and develop AoV calcific nodules as occurs in human CAVD. The role of BMP signaling in the development of CAVD was examined in porcine aortic valve interstitial cells (VICs) and Klotho(-/-) mice. APPROACH AND RESULTS: We show that activation of BMP signaling, as indicated by pSmad1/5/8 expression, precedes and later localizes with AoV calcification in Klotho(-/-) mice. In addition, cellular and extracellular matrix changes resembling features of normal bone formation are accompanied by increased osteochondrogenic gene induction in calcified Klotho(-/-) AoV. Likewise, osteogenic media treatment of porcine VICs results in BMP pathway activation, increased osteochondrogenic gene induction, and formation of calcific nodules in vitro. We demonstrate that genetic inactivation of the BMP type IA receptor in Klotho(-/-) aortic VICs, as well as BMP pathway inhibition of osteogenic media-treated aortic VICs in vitro, results in the inhibition of AoV calcification. CONCLUSIONS:BMP signaling and osteochondrogenic gene induction are active in calcified Klotho(-/-) AoV in vivo and calcified porcine aortic VICs in vitro. Importantly, BMP signaling is required for the development of AoV calcification in vitro and in vivo.
Authors: Elaine E Wirrig; M Victoria Gomez; Robert B Hinton; Katherine E Yutzey Journal: Arterioscler Thromb Vasc Biol Date: 2015-02-26 Impact factor: 8.311
Authors: Jason P Linefsky; Kevin D O'Brien; Ronit Katz; Ian H de Boer; Eddy Barasch; Nancy S Jenny; David S Siscovick; Bryan Kestenbaum Journal: J Am Coll Cardiol Date: 2011-07-12 Impact factor: 24.094
Authors: Ming Fang; Christina M Alfieri; Alexia Hulin; Simon J Conway; Katherine E Yutzey Journal: Arterioscler Thromb Vasc Biol Date: 2014-10-23 Impact factor: 8.311
Authors: M Kuro-o; Y Matsumura; H Aizawa; H Kawaguchi; T Suga; T Utsugi; Y Ohyama; M Kurabayashi; T Kaname; E Kume; H Iwasaki; A Iida; T Shiraki-Iida; S Nishikawa; R Nagai; Y I Nabeshima Journal: Nature Date: 1997-11-06 Impact factor: 49.962
Authors: Hongjun Liu; Maria M Fergusson; Rogerio M Castilho; Jie Liu; Liu Cao; Jichun Chen; Daniela Malide; Ilsa I Rovira; Daniel Schimel; Calvin J Kuo; J Silvio Gutkind; Paul M Hwang; Toren Finkel Journal: Science Date: 2007-08-10 Impact factor: 47.728
Authors: Alexia Hulin; Luis Hortells; M Victoria Gomez-Stallons; Anna O'Donnell; Kashish Chetal; Mike Adam; Patrizio Lancellotti; Cecile Oury; S Steven Potter; Nathan Salomonis; Katherine E Yutzey Journal: Development Date: 2019-03-12 Impact factor: 6.868
Authors: Jacob G Saxon; Daniel R Baer; Julie A Barton; Travis Hawkins; Bingruo Wu; Thomas C Trusk; Stephen E Harris; Bin Zhou; Yuji Mishina; Yukiko Sugi Journal: Dev Biol Date: 2017-08-06 Impact factor: 3.582
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311