Instituto Ciencias del Corazón (ICICOR), Valladolid, Spain.
Int J Cardiol. 2012 Jun 28;158(1):18-25. doi: 10.1016/j.ijcard.2010.12.089. Epub 2011 Jan 17.
Aortic stenosis shares some ethiopathological features with atherosclerosis and increasing evidence links Toll-like receptors (TLRs) to atherogenesis.
TLR-mediated inflammation and osteogenesis were investigated in human interstitial cells isolated from stenotic and non-stenotic aortic valves. TLR expression and signalling were evaluated by quantitative RT-PCR, flow cytometry, Western blot analysis, ELISA, and cytokine arrays. Osteogenesis was evaluated by measuring alkaline phosphatase activity.
Interstitial cells from control valves express most TLRs, being TLR4 the most abundant, whereas cells from stenotic valves express higher TLR4 and TLR2 and lower TLR5 and TLR9 transcript levels. When pro-inflammatory pathways were analyzed, we observed that TLR4, TLR2 and TLR3 ligands induced an early activation of NF-κB and p38 MAPK activation in cells from control and stenotic valves. Strikingly, when TLRs sensing viral patterns were studied, a sustained TLR3-mediated activation of NF-κB, a κB-independent induction of catalytically active cyclooxigenase (COX)-2 and ICAM-1 expression, and induction of expression of several chemokines were observed. TLR4, but not TLR2, engagement produced a similar but NF-κB-dependent effect. Moreover, TLR3 and TLR4 agonists induced alkaline phosphatase expression and activity.
Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis.
主动脉瓣狭窄与动脉粥样硬化具有一些相同的病因病理特征，越来越多的证据表明 Toll 样受体（TLR）与动脉粥样硬化的发生有关。
本研究旨在研究从狭窄和非狭窄主动脉瓣分离的人间质细胞中 TLR 介导的炎症和成骨作用。通过定量 RT-PCR、流式细胞术、Western blot 分析、ELISA 和细胞因子阵列评估 TLR 表达和信号转导。通过测量碱性磷酸酶活性来评估成骨作用。
来自对照瓣膜的间质细胞表达大多数 TLR，其中 TLR4 最为丰富，而来自狭窄瓣膜的细胞表达更高水平的 TLR4 和 TLR2，以及更低水平的 TLR5 和 TLR9 转录物。当分析促炎途径时，我们观察到 TLR4、TLR2 和 TLR3 配体在来自对照和狭窄瓣膜的细胞中诱导 NF-κB 的早期激活和 p38 MAPK 的激活。引人注目的是，当研究 TLR 感知病毒模式时，观察到 TLR3 介导的 NF-κB 的持续激活、非依赖性诱导具有催化活性的环氧化酶（COX）-2 和 ICAM-1 的表达，以及几种趋化因子的诱导表达。TLR4，但不是 TLR2，参与产生类似但 NF-κB 依赖性的作用。此外，TLR3 和 TLR4 激动剂诱导碱性磷酸酶的表达和活性。
主动脉瓣间质细胞暴露于病毒和革兰氏阴性细菌分子模式会引起独特且长期的 TLR 介导的促炎和促成骨反应，这可能与退行性主动脉瓣狭窄的发病机制有关。
