ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular...

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Biology
• Cellular Phenotypic Transition

Background:

• Extracellular matrix proteinases are key in calcific aortic valve disease (CAVD) pathogenesis.
• ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) degrades extracellular matrix proteins, including matrilin 2.
• The role of the ADAMTS5/matrilin 2 axis in valvular interstitial cell (VIC) phenotype changes in CAVD is not fully understood.

Purpose of the Study:

• To investigate the role of the ADAMTS5/matrilin 2 axis in mediating VIC phenotype transition in CAVD.
• To elucidate the molecular mechanisms by which matrilin 2 influences VICs.

Main Methods:

• Quantification of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) in human aortic valve tissues and VICs.
• In vitro studies involving normal VICs treated with matrilin 2, with or without ADAMTS5 knockdown.
• Analysis of signaling pathways including Toll-like receptors, NF-κB, and NFATc1.
• Assessment of osteogenic markers and calcium deposition.

Main Results:

• Calcified valves showed decreased ADAMTS5 and increased matrilin 2 and α-SMA.
• Matrilin 2 treatment induced α-SMA, runx2, and alkaline phosphatase in VICs via TLR2/4.
• ADAMTS5 knockdown potentiated matrilin 2 effects.
• Matrilin 2 activated NF-κB and NFATc1, crucial for VIC phenotype change.
• α-SMA levels correlated with pro-osteogenic factors and calcification.

Conclusions:

• Matrilin 2 induces VIC myofibroblastic transition and pro-osteogenic activity through NF-κB and NFATc1.
• VIC myofibroblastic transition is a key mechanism for increased osteogenic activity.
• Matrilin 2 accumulation with relative ADAMTS5 deficiency likely contributes to CAVD progression.