The Pathogenic Roles of Local Vitamin D Metabolism Defect in Valve Inflammation and Calcification

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Immunology

Background:

• Calcific aortic valve disease (CAVD) is a common condition leading to heart failure, with unclear causes and no current medical treatments.
• Understanding the cellular mechanisms driving CAVD is crucial for developing effective therapies.

Purpose of the Study:

• To elucidate the cellular and molecular pathogenesis of calcific aortic valve disease (CAVD).
• To identify potential therapeutic targets for preventing or treating CAVD.

Main Methods:

• A high-phosphate-diet-induced valvular calcification mouse model was employed.
• Single-cell profiling and genetic tracing were used to analyze cellular changes.
• Valve interstitial cells (VICs) and immune cell responses were investigated.
• The effects of active and inactive vitamin D were assessed in vivo.

Main Results:

• Two subpopulations of Prrx1+Acta2- VICs were identified undergoing osteogenic differentiation.
• Elevated phosphate suppressed vitamin D metabolism genes in VICs, activating local immune cells and endothelial cells.
• Inflammatory cytokines and phosphate synergistically promoted VIC osteogenic differentiation via ERK signaling.
• Active vitamin D suppressed inflammation and reduced valvular calcification, unlike the inactive form.
• Similar cellular and molecular changes were observed in human CAVD patient samples.

Conclusions:

• This study reveals the cellular and molecular basis of valvular calcification in CAVD.
• Active vitamin D demonstrates potential as a therapeutic agent to prevent CAVD development by suppressing inflammation and VIC osteogenic differentiation.