Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification

M. V. Gomez-Stallons, Elaine E. Wirrig-Schwendeman, Keira R. Hassel, Simon Conway, Katherine E. Yutzey

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
StateAccepted/In press - May 19 2016

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Bone Morphogenetic Proteins
Aortic Valve
Aortic Diseases
Swine
Osteogenesis
Calcification of Aortic Valve
Type I Bone Morphogenetic Protein Receptors
Genes
Premature Aging
Heart Valve Diseases
Aortic Valve Stenosis
Extracellular Matrix

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification. / Gomez-Stallons, M. V.; Wirrig-Schwendeman, Elaine E.; Hassel, Keira R.; Conway, Simon; Yutzey, Katherine E.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, 19.05.2016.

Research output: Contribution to journalArticle

Gomez-Stallons, M. V. ; Wirrig-Schwendeman, Elaine E. ; Hassel, Keira R. ; Conway, Simon ; Yutzey, Katherine E. / Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016.
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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.",
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N2 - 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.

AB - 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.

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