1. TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction.
- Author
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Lee GL, Yeh CC, Wu JY, Lin HC, Wang YF, Kuo YY, Hsieh YT, Hsu YJ, and Kuo CC
- Subjects
- Animals, Aortic Diseases etiology, Aortic Diseases genetics, Aortic Diseases pathology, Aortic Diseases prevention & control, Apolipoproteins E deficiency, Atherosclerosis etiology, Atherosclerosis genetics, Atherosclerosis prevention & control, Calcinosis genetics, Cells, Cultured, Cholesterol, Dietary toxicity, Diet, High-Fat adverse effects, Dietary Fats toxicity, Gene Expression Regulation, Male, Mice, Mice, Inbred C57BL, NF-kappa B metabolism, Osteoprotegerin genetics, RANK Ligand genetics, Random Allocation, Atherosclerosis pathology, Calcinosis metabolism, Calcinosis pathology, Chondrogenesis physiology, Interleukin-6 physiology, MAP Kinase Signaling System, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle metabolism, Osteoprotegerin biosynthesis, RANK Ligand biosynthesis, Toll-Like Receptor 2 physiology
- Abstract
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 κB 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-κB (nuclear factor κB) 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.- Published
- 2019
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