Abstract 14539: Adamts5 Deficiency in Human Aortic Valves Elevates the Pro-osteogenic Activity Through Matrilin2-mediated Cellular Phenotypic Transition
The transition of aortic valvular interstitial cells (AVICs) to myofibroblastic and osteoblast-like phenotypes plays a critical role in the progression of calcific aortic valve disease (CAVD). Understanding of the mechanism underlying VIC phenotypic transition may lead to the development of therapeutic approaches for prevention of CAVD progression. Extracellular matrix proteinases are implicated in the pathogenesis of CAVD. The ADAMTS5 (A Disintegrin and Metalloproteinase with Thrombospondin motifs 5) is a secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin2. The
Objective: of this study was to determine the role of the ADAMTS5/matrilin2 axis in mediating the phenotype transitions of AVICs associated with CAVD.
Methods and Results: Levels of ADAMTS5, matrilin2 and α-smooth muscle actin (α-SMA) were evaluated in calcified and normal human aortic valve tissues and cells. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin2 and α-SMA. Treatment of normal AVICs with soluble matrilin2 caused an increase in α-SMA level through Toll-like receptor (TLR) 2 and 4, which was accompanied by up-regulation of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). In addition, ADAMTS5 knockdown in AVICs of normal valves enhanced the effect of matrilin2. Matrilin2 activated NF-κB and nuclear factor of activated T cells complex 1 (NFATc1), and induced the interaction of these two nuclear factors. Inhibition of either NF-κB or NFATc1 suppressed matrilin2’s effect on VIC phenotypic change. Knockdown of α-SMA reduced and over-expression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposition in human VICs.
Conclusions: These novel findings demonstrate that matrilin2 induces myofibroblastic transition and elevates pro-osteogenic activity in human AVICs through TLRs and that myofibroblastic transition is an important mechanism of elevating AVIC pro-osteogenic activity. NF-κB and NFATc1 coordinately mediate the effect of matrilin2 in AVICs. Matrilin2 accumulation associated with ADAMTS5 deficiency may promote aortic valve calcification through inducing AVIC myofibroblastic transition.
Author Disclosures: F. Li: None. R. Song: None. L. Ao: None. T. Reece: None. J.C. Cleveland: None. N. Dong: None. D. Fullerton: None. X. Meng: None.
- © 2016 by American Heart Association, Inc.