TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction
TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction
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DOI：
10.1161/atvbaha.118.311874
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发表时间：
2019-03-01
影响因子：
8.7
通讯作者：
Kuo, Cheng-Chin
中科院分区：
文献类型：
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作者：
Lee, Guan-Lin;Yeh, Chang-Ching;Kuo, Cheng-Chin
目的血管平滑肌细胞（VSMC）向骨软骨形成表型的转变是动脉钙化的第一步，而动脉钙化与心血管疾病相关的发病率和死亡率高度相关。TLR2 （toll样受体2）在血管疾病的发生发展中起致病作用，但其在动脉钙化和VSMCs中的调节作用尚不清楚。我们假设tlr2介导的炎症参与了动脉粥样硬化动脉钙化和VSMC钙化的介导。方法和结果我们发现，与ApoE（-/-）小鼠相比，小鼠的ApoE(-/-)Tlr2（-/-）基因型在起始阶段抑制高脂肪饮食诱导的动脉粥样硬化斑块形成，但逐渐丧失其预防能力。然而，TLR2缺乏禁止高脂肪饮食诱导的晚期动脉粥样硬化钙化、软骨性化生和钙化病变中OPG（骨保护素）下调。在钙化培养基中培养VSMC发现，TLR2激动剂显著增加VSMC钙化和软骨分化。此外，TLR2缺乏抑制了TLR2激动剂介导的VSMC软骨分化和随之而来的钙化，这是通过IL（白细胞介素）-6介导的RANKL（核因子B配体受体激活剂）诱导和OPG抑制的协同作用引发的。药物抑制剂抑制实验表明，il -6介导的RANKL诱导是通过p38和ERK1/2（细胞外信号调节激酶1/2）途径进行的，而OPG是通过ERK1/2介导的NF-B（核因子B）依赖性信号传导来抑制的。结论在配体结合上，TLR2激活p38和ERK1/2信号，选择性调节il -6介导的RANKL上调和OPG下调。这些信号通路协同作用诱导VSMCs的软骨转分化，进而导致动脉粥样硬化发病过程中的血管钙化。
Objective Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification.Approach and Results We found that ApoE(-/-)Tlr2(-/-) genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE(-/-) mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor B ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-B (nuclear factor B) dependent signaling mediated by ERK1/2.Conclusions We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.