Role of Runx2 in Calcific Aortic Valve Disease in Mouse Models

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Biomedical Research

Background:

• Calcific aortic valve disease (CAVD) is a prevalent condition in aging populations, characterized by extracellular matrix remodeling, osteochondrogenic differentiation, and calcification of aortic valves.
• These pathological changes can lead to aortic sclerosis, aortic stenosis (AS), and ultimately heart failure.
• Runt-related transcription factor 2 (Runx2) is highly expressed in calcified aortic valves, but its precise role in CAVD progression remains unclear.

Purpose of the Study:

• To investigate the definitive role of Runx2 in the molecular, histological, and functional progression of calcific aortic valve disease (CAVD).
• To determine the cellular origin of Runx2-expressing osteochondrogenic cells within diseased aortic valves.
• To assess the impact of Runx2 depletion on aortic valve function and calcification in mouse models of CAVD.

Main Methods:

• Utilized lineage tracing studies to identify the source of Runx2+ osteochondrogenic cells in LDLr-/- mouse aortic valves.
• Employed constitutive and transient conditional knockout mouse models with Runx2 depletion in activated valvular interstitial cells (aVICs) and sinus wall cells.
• Examined gene expression, blood flow dynamics, calcification, and histology in hyperlipidemic mice fed a diabetogenic diet.

Main Results:

• Activated valvular interstitial cells (aVICs) and sinus wall cells were identified as the origin of Runx2+ osteochondrogenic cells in diseased aortic valves.
• Conditional Runx2 depletion in aVICs and sinus wall cells reduced osteochondrogenic gene expression and significantly improved aortic valve function (peak velocity, mean velocity, mean gradient) in a mouse model of CAVD.
• Transient Runx2 depletion significantly decreased leaflet hinge and sinus wall calcification, although cusp calcification and thickness were unaffected.

Conclusions:

• Runx2 is expressed early in aortic valve disease and is essential for the osteochondrogenic differentiation of aVICs and sinus wall cells.
• Transient depletion of Runx2 in aVICs and sinus wall cells ameliorates aortic valve dysfunction in a mouse model of CAVD.
• Leaflet hinge and sinus wall calcification, even without significant cusp calcification, can lead to substantial valve dysfunction.