Liu Qing, Li Jianping, Liang Qiaoli, Wang Dawei, Luo Yi, Yu Fang, Janicki Joseph S, Fan Daping
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States; Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, United States.
Vascul Pharmacol. 2015 Apr-Jun;67-69:59-66. doi: 10.1016/j.vph.2015.03.015. Epub 2015 Apr 11.
Vascular smooth muscle cells (VSMCs) play a crucial role in atherosclerotic lesion formation. Sparstolonin B (SsnB) is a TLR2/TLR4 antagonist that inhibits inflammatory responses in multiple cell types. Herein, we investigated if SsnB inhibited VSMC proliferation, migration, inflammatory response and lipid accumulation. We found that SsnB suppressed VSMC proliferation and migration induced by PDGF. SsnB significantly suppressed the expression of MCP-1, TNFα and IL-6 in VSMCs stimulated by either lipopolysaccharide (LPS) or PDGF. Erk1/2 and Akt signaling pathways, which are responsible for the VSMC inflammatory response, were activated by LPS or PDGF stimulation, and SsnB significantly inhibited their activation. SsnB also substantially suppressed the intracellular cholesterol accumulation in VSMCs loaded with acetylated LDL. Mechanistically, SsnB remarkably repressed LPS-induced up-regulation of CD36, which is responsible for lipid uptake, and dramatically reversed LPS-induced inhibition of ABCA1, which promotes the efflux of intracellular free cholesterol. In conclusion, our results indicate that SsnB significantly inhibits VSMC proliferation, migration, inflammatory responses and lipid accumulation. Along with the previously reported anti-inflammatory activities of SsnB on macrophages and vascular endothelial cells, our data strongly suggest that SsnB may be developed as a new anti-atherogenic therapy.
血管平滑肌细胞（VSMCs）在动脉粥样硬化病变形成中起关键作用。斯巴司他汀B（SsnB）是一种TLR2/TLR4拮抗剂，可抑制多种细胞类型的炎症反应。在此，我们研究了SsnB是否能抑制血管平滑肌细胞的增殖、迁移、炎症反应和脂质积累。我们发现SsnB可抑制血小板衍生生长因子（PDGF）诱导的血管平滑肌细胞增殖和迁移。SsnB显著抑制脂多糖（LPS）或PDGF刺激的血管平滑肌细胞中单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）的表达。负责血管平滑肌细胞炎症反应的细胞外信号调节激酶1/2（Erk1/2）和蛋白激酶B（Akt）信号通路被LPS或PDGF刺激激活，而SsnB可显著抑制它们的激活。SsnB还能显著抑制加载乙酰化低密度脂蛋白（LDL）的血管平滑肌细胞内胆固醇的积累。机制上，SsnB显著抑制LPS诱导的负责脂质摄取的CD36上调，并显著逆转LPS诱导的促进细胞内游离胆固醇外流的ATP结合盒转运体A1（ABCA1）的抑制作用。总之，我们的结果表明SsnB可显著抑制血管平滑肌细胞的增殖、迁移、炎症反应和脂质积累。连同先前报道的SsnB对巨噬细胞和血管内皮细胞的抗炎活性，我们的数据强烈表明SsnB可能被开发为一种新的抗动脉粥样硬化疗法。
