Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification

Danielle J Huk; Blair F Austin; Tori E Horne; Robert B Hinton; William C Ray; Donald D Heistad; Joy Lincoln

doi:10.1161/ATVBAHA.115.306091

Back

Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification

Journal article

Open access

Peer reviewed

Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification

Danielle J Huk, Blair F Austin, Tori E Horne, Robert B Hinton, William C Ray, Donald D Heistad and Joy Lincoln

Arteriosclerosis, thrombosis, and vascular biology, Vol.36(2), pp.328-338

02/2016

DOI: 10.1161/ATVBAHA.115.306091

PMCID: PMC4732913

PMID: 26634652

Files and links (1)

url

https://doi.org/10.1161/ATVBAHA.115.306091View

Published (Version of record) Open Access

Abstract

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. 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. 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.

Calcinosis - genetics

Aortic Valve Stenosis - genetics

Humans

Transforming Growth Factor beta1 - metabolism

Aortic Valve - pathology

Aortic Valve Stenosis - prevention & control

Collagen Type II - metabolism

Transfection

Time Factors

rho-Associated Kinases - metabolism

Swine

Active Transport, Cell Nucleus

Calcinosis - metabolism

SOX9 Transcription Factor - metabolism

Paracrine Communication

Signal Transduction

Endothelial Cells - metabolism

Tissue Culture Techniques

Mice, Inbred C57BL

Cells, Cultured

Transforming Growth Factor beta1 - genetics

Aortic Valve - metabolism

Collagen Type II - genetics

Mice, Knockout

Animals

Aortic Valve Stenosis - pathology

Aortic Valve Stenosis - metabolism

Calcinosis - prevention & control

Mice

Calcinosis - pathology

Endothelial Cells - pathology

SOX9 Transcription Factor - genetics

Details

Title: Subtitle: Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification
Creators: Danielle J Huk - 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.)
Blair F Austin - 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.)
Tori E Horne - 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.)
Robert B Hinton - 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.)
William C Ray - 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.)
Donald D Heistad - 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 - 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
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.36(2), pp.328-338
DOI: 10.1161/ATVBAHA.115.306091
PMID: 26634652
PMCID: PMC4732913
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Publisher: United States
Grant note: R01 HL091878 / NHLBI NIH HHS HL62984 / NHLBI NIH HHS HL127033 / NHLBI NIH HHS HL091878 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R01 HL127033 / NHLBI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040003902771

Metrics

36 Record Views

54 Times Cited - Web of Science