Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Vascul Pharmacol. 2019 Oct;121:106579. doi: 10.1016/j.vph.2019.106579. Epub 2019 Jul 15.
Foam cell formation and monocytes adhesion are key events in pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) are an important origin of foam cells besides macrophages. Fibronectin type III domain containing protein 5 (FNDC5) is a protein, which induces browning of fat and attenuates glucose/lipid metabolic derangements in obese mice. The present study was designed to determine the roles of FNDC5 in inhibiting foam cell formation and monocyte adhesion in VSMCs and its underlying mechanisms. Oxidized low-density lipoprotein (oxLDL) was used to induce foam cell formation and monocyte adhesion in human aortic VSMCs. Foam cell formation was evaluated by intracellular lipid droplets, cholesterol contents, and mRNA levels of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT-1) and ATP binding cassette transporter A-1 (ABCA-1). Monocyte adhesion was evaluated by the number of monocytes adhered to VSMCs and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). FNDC5 inhibited oxLDL-induced foam cell formation, monocyte adhesion, ABCA-1 mRNA downregulation, and ACAT-1, MCP-1 and VCAM-1 mRNA upregulation in VSMCs. It inhibited oxLDL-induced p65-NFκB nuclear translocation, NLRP3 upregulation, caspase-1 and IL-1β production. Inhibition of NFκB with BMS-345541 or inhibition of NLRP3 inflammasome with MCC950 showed similar effects to FNDC5 in attenuating the oxLDL-induced foam cell formation, monocyte adhesion, and caspase-1 and IL-1β production. The oxLDL-induced NLRP3 upregulation was prevented by BMS-345541 rather than MCC950. These results indicate that FNDC5 inhibits oxLDL-induced foam cell formation and monocyte adhesion in VSMCs via suppressing NFκB-mediated NLRP3 upregulation and IL-1β production.
泡沫细胞的形成和单核细胞黏附是动脉粥样硬化发病机制中的关键事件。血管平滑肌细胞（VSMCs）是除巨噬细胞之外泡沫细胞的重要来源。纤维连接蛋白 III 型结构域包含蛋白 5（FNDC5）是一种蛋白，它可诱导脂肪褐变，并减轻肥胖小鼠的葡萄糖/脂质代谢紊乱。本研究旨在确定 FNDC5 在抑制 VSMCs 中泡沫细胞形成和单核细胞黏附中的作用及其潜在机制。使用氧化型低密度脂蛋白（oxLDL）诱导人主动脉 VSMCs 中泡沫细胞形成和单核细胞黏附。通过细胞内脂滴、胆固醇含量以及酰基辅酶 A：胆固醇酰基转移酶 1（ACAT-1）和三磷酸腺苷结合盒转运体 A-1（ABCA-1）的 mRNA 水平评估泡沫细胞形成。通过黏附于 VSMCs 的单核细胞数量和单核细胞趋化蛋白-1（MCP-1）和血管细胞黏附分子-1（VCAM-1）的 mRNA 水平评估单核细胞黏附。FNDC5 抑制 oxLDL 诱导的 VSMCs 中泡沫细胞形成、单核细胞黏附、ABCA-1 mRNA 下调以及 ACAT-1、MCP-1 和 VCAM-1 mRNA 上调。它抑制 oxLDL 诱导的 p65-NFκB 核易位、NLRP3 上调、半胱天冬酶-1 和 IL-1β 的产生。用 BMS-345541 抑制 NFκB 或用 MCC950 抑制 NLRP3 炎性小体，与 FNDC5 一样，可减轻 oxLDL 诱导的泡沫细胞形成、单核细胞黏附和半胱天冬酶-1 和 IL-1β 的产生。BMS-345541 而非 MCC950 可阻止 oxLDL 诱导的 NLRP3 上调。这些结果表明，FNDC5 通过抑制 NFκB 介导的 NLRP3 上调和 IL-1β 的产生来抑制 oxLDL 诱导的 VSMCs 中泡沫细胞形成和单核细胞黏附。
