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

ABSTRACT: OBJECTIVE:Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease. APPROACH AND RESULTS:Levels of ADAMTS5, matrilin 2, and ?-SMA (?-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and ?-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in ?-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) ?B and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-?B or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of ?-SMA reduced and overexpression of ?-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. CONCLUSIONS:Matrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-?B and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.

SUBMITTER: Li F 

PROVIDER: S-EPMC5516888 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature