JOURNAL ARTICLE

TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification Via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction

Guan-Lin Lee, Chang-Ching Yeh, Jing-Yiing Wu, Hui-Chen Lin, Yi-Fu Wang, Ya-Yi Kuo, Yi-Ting Hsieh, Yu-Juei Hsu, Cheng-Chin Kuo
Arteriosclerosis, Thrombosis, and Vascular Biology 2019 January 10, : ATVBAHA118311874
30626205
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 Result s-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 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.

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