Department of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USA.
Int J Mol Sci. 2020 Feb 14;21(4):1276. doi: 10.3390/ijms21041276.
Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs.
Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves.
AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity.
The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.
钙化性主动脉瓣疾病（CAVD）是一种慢性炎症性疾病，表现为进行性瓣叶纤维化和钙化。瓣膜组织中的炎症环境促进纤维化和钙化。主动脉瓣间质细胞（AVIC）增殖和细胞外基质（ECM）蛋白过度产生导致瓣叶增厚。然而，AVIC 纤维生成活性升高的机制尚不清楚。最近，我们观察到病变主动脉瓣中的 AVIC 表达更高水平的神经营养因子 3（NT3），并且 NT3 对人 AVIC 具有促成骨和成纤维作用。
促炎刺激物上调 AVIC 中的 NT3 产生，以促进人主动脉瓣的纤维生成活性。
从正常人类主动脉瓣中分离出 AVIC，并使用脂多糖（LPS，0.20μg/ml）处理。LPS 诱导 TLR4 依赖性 NT3 产生。LPS 对 Akt 和细胞外信号调节蛋白激酶 1 和 2（ERK1/2）途径的抑制作用消除了这种 LPS 作用。LPS 刺激人 AVIC 中的 TLR4 导致增殖率增加，基质金属蛋白酶-9（MMP-9）和 III 型胶原的产生增加，以及胶原沉积增加。LPS 刺激 TLR4 导致 AVIC 增殖呈原肌球蛋白受体激酶（Trk）依赖性。NT3 的中和或 Trk 的抑制抑制 LPS 诱导的 AVIC 纤维生成活性。
TLR4 在人 AVIC 中的刺激上调 NT3 表达并促进细胞增殖和胶原沉积。NT3-Trk 级联在 TLR4 介导的人 AVIC 纤维生成活性升高中起关键作用。内源性 TLR4 激活剂上调的 NT3 产生可能导致与 CAVD 进展相关的主动脉瓣纤维化。
