TLR2介导的血管平滑肌细胞向肌成纤维细胞表型转化在泡沫细胞形成中的作用和机制

Vascular smooth muscle cells（VSMCs） phenotypic switching plays a major role in foam cells formation. Prostate SMCs stimulated by LPS have been reported to dedifferentiate from a contractile to a myofibroblastic-like phenotype and secreting cytokines, with the TLR4 signaling pathway being involved in this response. Balloon Angioplasty was used to induce pig coronary injury. Under hyperlipidemic conditions, lipid accumulated in the regions enriched by myofibroblasts. Our previous study disclosed that TLR4 signing initiated by oxLDL was involved in VSMC-derived foam cells formation. Herein, we postulate that VSMCs are capable to convert to myofibroblasts-like phenotype during the process of foam cells formation, and TLR2 signing may involve in this pathologic process. In the present study, both ApoE-/-TLR2-/- mice and genetic approaches will be used to evaluate the potential role of TLR2 signing in VSMCs phenotypic switching to fibroblasts, and in atherosclerotic lesion formation. Additionally, wild type and TLR2-/- VSMCs will be stimulated with oxidized low-density lipoprotein(oxLDL). We will further determine that TLR2 promotes VSMCs converted to myofibroblast-like phenotype in vitro. TLR2 knockout inhibits VSMCs phenotype conversion and foam cells formation. We aim to disclose the underlying molecular mechanism of foam cells formation, and provide a promising target for the prevention and treatment of atherosclerosis.

血管平滑肌细胞发生表型转化是泡沫细胞形成的重要病理过程。研究报道，LPS可诱导前列腺SMCs向肌成纤维细胞表型转化。球囊诱导猪冠脉损伤，在血脂偏高组中，肌成纤维细胞富集区见大量脂质沉积。我们前期研究发现，oxLDL通过活化TLR4通路促进平滑肌源性泡沫细胞的形成。我们推测，泡沫细胞形成过程中oxLDL促进VSMCs向肌成纤维细胞表型转化，其机制可能与TLR2通路活化有关。为此本项目拟利用①基因工程技术和ApoE-/-TLR2-/-基因双敲小鼠，高脂饮食建立动脉粥样硬化模型，观察AS病灶中TLR2通路活化对VSMCs向肌成纤维细胞表型转化的影响；②oxLDL刺激培养野生型及TLR2-/-VSMCs，进一步证实VSMCs可转化为肌成纤维细胞表型，TLR2基因敲除后抑制VSMCs表型发生转化，并抑制泡沫细胞的形成。该项目旨在深入研究泡沫细胞形成的分子机制，为动脉粥样硬化的防治提供新的靶点。