Danielle J Huk1, Blair F Austin1, Tori E Horne1, Robert B Hinton1, William C Ray1, Donald D Heistad1, Joy Lincoln2. 1. From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children's Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children's Hospital Research Institute, Columbus, OH (W.C.R.); The Ohio State University Interdisciplinary Graduate Program in Biophysics, Columbus, OH (W.C.R.); Department of Pediatrics, The Ohio State University, Columbus, OH (W.C.R., J.L.); and Division of Cardiovascular Medicine and Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.). 2. From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children's Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children's Hospital Research Institute, Columbus, OH (W.C.R.); The Ohio State University Interdisciplinary Graduate Program in Biophysics, Columbus, OH (W.C.R.); Department of Pediatrics, The Ohio State University, Columbus, OH (W.C.R., J.L.); and Division of Cardiovascular Medicine and Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA (D.D.H.). joy.lincoln@nationwidechildrens.org.
Abstract
OBJECTIVE: Aortic valve disease, including calcification, affects >2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown. APPROACH AND RESULTS: Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of Tgfβ1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease. CONCLUSIONS: Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.
OBJECTIVE:Aortic valve disease, including calcification, affects >2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown. APPROACH AND RESULTS: Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of Tgfβ1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease. CONCLUSIONS: Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.
Authors: Alexia Hulin; Christophe F Deroanne; Charles A Lambert; Bruno Dumont; Vincent Castronovo; Jean-Olivier Defraigne; Betty V Nusgens; Marc A Radermecker; Alain C Colige Journal: Cardiovasc Res Date: 2011-12-16 Impact factor: 10.787
Authors: Jennifer Richards; Ismail El-Hamamsy; Si Chen; Zubair Sarang; Padmini Sarathchandra; Magdi H Yacoub; Adrian H Chester; Jonathan T Butcher Journal: Am J Pathol Date: 2013-03-13 Impact factor: 4.307
Authors: Michael A Hagler; Thomas M Hadley; Heyu Zhang; Kashish Mehra; Carolyn M Roos; Hartzell V Schaff; Rakesh M Suri; Jordan D Miller Journal: Cardiovasc Res Date: 2013-04-03 Impact factor: 10.787
Authors: Adrian H Chester; Ismail El-Hamamsy; Jonathan T Butcher; Najma Latif; Sergio Bertazzo; Magdi H Yacoub Journal: Glob Cardiol Sci Pract Date: 2014-01-29
Authors: Charu Munjal; Amy M Opoka; Hanna Osinska; Jeanne F James; Giorgio M Bressan; Robert B Hinton Journal: Dis Model Mech Date: 2014-08 Impact factor: 5.758
Authors: Joyce Bischoff; Guillem Casanovas; Jill Wylie-Sears; Dae-Hee Kim; Philipp E Bartko; J Luis Guerrero; Jacob P Dal-Bianco; Jonathan Beaudoin; Michael L Garcia; Suzanne M Sullivan; Margo M Seybolt; Brittan A Morris; Joshua Keegan; Whitney S Irvin; Elena Aikawa; Robert A Levine Journal: Circ Res Date: 2016-10-06 Impact factor: 17.367
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