Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification

Area of Science:

• Cardiovascular Biology
• Bone Biology
• Biomaterials Science

Background:

• Calcific aortic valve disease (CAVD) is a prevalent heart valve condition characterized by calcific nodules leading to aortic valve stenosis.
• The underlying mechanisms of CAVD remain largely unknown, though studies suggest a role for bone morphogenetic protein (BMP) signaling.
• Klotho-deficient mice exhibit premature aging and develop aortic valve calcification, mirroring human CAVD.

Purpose of the Study:

• To investigate the role of BMP signaling in the development of CAVD.
• To examine BMP signaling activation and its correlation with calcification in Klotho-deficient mice and porcine aortic valve interstitial cells (VICs).

Main Methods:

• Analysis of pSmad1/5/8 expression in Klotho(-/-) mice to assess BMP signaling activation.
• In vitro studies using porcine VICs treated with osteogenic media.
• Genetic inactivation of the BMP type IA receptor in Klotho(-/-) aortic VICs.
• Inhibition of BMP pathway in osteogenic media-treated VICs.

Main Results:

• BMP signaling activation (pSmad1/5/8 expression) precedes and co-localizes with aortic valve calcification in Klotho(-/-) mice.
• Calcified Klotho(-/-) aortic valves show cellular and extracellular matrix changes resembling bone formation, with increased osteochondrogenic gene expression.
• In vitro, osteogenic media induced BMP pathway activation, osteochondrogenic gene expression, and calcific nodule formation in porcine VICs.
• Genetic inactivation or pharmacological inhibition of BMP signaling in VICs prevented aortic valve calcification.

Conclusions:

• BMP signaling and osteochondrogenic gene induction are active in calcified aortic valves in both Klotho(-/-) mice and porcine VICs.
• BMP signaling is essential for the development of aortic valve calcification in vitro and in vivo.
• Targeting BMP signaling represents a potential therapeutic strategy for CAVD.