Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1580-90. doi: 10.1161/ATVBAHA.112.300912. Epub 2013 May 2.
Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro-osteogenic response of human AVICs.
AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro-osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, extracellular signal-regulated protein kinases 1/2 (ERK1/2) and nuclear factor-κB phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-κB also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide.
Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro-osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-κB activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease.
钙化性主动脉瓣疾病是老年人的主要心血管疾病，瓣膜进行性钙化导致瓣功能衰竭。狭窄瓣膜的主动脉瓣间质细胞（AVIC）在 Toll 样受体 4 刺激下表达更高水平的骨形态发生蛋白-2。我们最近发现，Toll 样受体 4 在人 AVIC 中与 Notch1 相互作用。本研究检验了 Notch1 促进人 AVIC 成骨前体反应的假说。
从病变人瓣膜中分离出的 AVIC 在脂多糖刺激后表达更高水平的骨形态发生蛋白-2 和碱性磷酸酶。增强的成骨前体反应与 Notch1 细胞水平升高和脂多糖刺激后 Notch1 切割增强相关。Notch1 的抑制或沉默抑制了病变细胞的成骨前体反应，而 Notch1 配体 Jagged1 增强了从正常人瓣膜中分离出的 AVIC 的反应。有趣的是，脂多糖诱导的细胞外信号调节蛋白激酶 1/2（ERK1/2）和核因子-κB 磷酸化通过 Notch1 的抑制或沉默显著降低，并通过 Jagged1 增强。ERK1/2 或核因子-κB 的抑制也降低了脂多糖诱导的骨形态发生蛋白-2 和碱性磷酸酶的表达。
Notch1 介导人 AVIC 对 Toll 样受体 4 刺激的成骨前体反应。升高的 Notch1 水平和增强的 Notch1 激活通过调节 ERK1/2 和核因子-κB 激活，在增强狭窄瓣膜 AVIC 的成骨前体反应中起主要作用。这些途径可能是预防钙化性主动脉瓣疾病进展的潜在治疗靶点。
