Abstract 13343: Up-regulated Expression of Neurotrophin 3 in the Interstitial Cells of Stenotic Aortic Valves May Promote Valvular Fibrosis
Introduction: Aortic valve stenosis is characterized by valvular fibrosis, calci[[Unable to Display Character: ﬁ]]cation and extracellular matrix (ECM) remodeling. Aortic valve interstitial cell (AVIC) proliferation and over-production of ECM proteins result in valve thickening and fibrosis. However, the factors that mediate AVIC proliferation and ECM protein expression need to be identified. Our previous work demonstrated that human AVICs express Toll-like receptor (TLR4), and TLR4 signaling can be activated by several endogenous proteins associated with aortic valve stenosis, including soluble biglycan and oxidized low density lipoprotein. Recently, we observed that AVICs of stenotic aortic valve express higher levels of NT3. It remains unknown whether NT3 induces the fibrogenic responses in AVICs and whether stimulation of TLR4 up-regulates NT3 expression in human AVICs.
Hypothesis: Neurotrophin 3 induces AVIC proliferation and ECM protein production, and contributes to the mechanism of AVIC fibrogenic responses to TLR4 stimulation.
Methods and Results: AVICs were isolated from normal human aortic valve leaflets. Stimulation of AVICs with TLR4 agonist lipopolysaccharide (LPS, 0.20 μg/ml) increased the expression NT3 through a mechanism involving the ERK1/2, p38 MAPK and NF-κB pathways. NT3-neutrolizing antibody and the neurotrophin receptor, Trk, inhibitor (K252a, 0.20 μmol/L) suppressed LPS-induced AVIC proliferation and the expression of MMP-9 and collagen III. Stimulation of AVICs with NT3 (0.10 μg/ml) induced proliferation and the expression of MMP-9 and collagen III that are Trk-dependent and are associated with Akt phosphorylation and an elevation in the levels of cyclin D1. Inhibition of Akt or cyclin D1 suppressed NT3-induced proliferation and ECM protein production.
Conclusions: Stimulation of TLR4 promotes human AVIC proliferation and ECM protein production through up-regulation of NT3 expression. The ERK1/2, p38 MAPK and NF-κB pathways mediate NT3 expression in human AVICs in response to TLR4 stimulation. NT3 induces AVIC proliferation and ECM protein expression via the Trk-Akt-cyclin D1 axis. Thus, NT3 is a pro-fibrogenic mediator in the aortic valve, and over-production of NT3 may promote the progression of aortic valve stenosis.
Author Disclosures: Q. Yao: None. X. yu: None. X. Meng: None. D. Fullerton: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.