Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea; Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.
Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey.
Biomed J. 2023 Apr;46(2):100534. doi: 10.1016/j.bj.2022.04.005. Epub 2022 Apr 26.
Capmatinib (CAP) is a drug that has been used to treat non-small cell lung cancer (NSCLC) in adults. Presently, its novel effects on skeletal muscle insulin signaling, inflammation, and lipogenesis in adipocytes have been uncovered with a perspective of drug repositioning. However, the impact of CAP on LPS-mediated interaction between human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes has yet to be investigated.
HUVECs and THP-1 monocytes were treated with LPS and CAP. The protein expression levels were determined using Western blotting. Target protein knockdown was conducted using small interfering (si) RNA transfection. Interactions between HUVECs and THP-1 cells were assayed using green fluorescent dye.
This study found that CAP treatment ameliorated cell adhesion between THP-1 monocytes and HUVECs and the expression of adhesive molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, phosphorylation of inflammatory markers, such as NFκB and IκB as well as TNFα and monocyte chemoattractant protein-1 (MCP-1) released from HUVECs and THP-1 monocytes, was prevented by CAP treatment. Treatment with CAP augmented PPARδ and IL-10 expression. siRNA-associated suppression of PPARδ and IL-10 abolished the effects of CAP on cell interaction between HUVECs and THP-1 cells and inflammatory responses. Further, PPARδ siRNA mitigated CAP-mediated induction of IL-10 expression.
These findings imply that CAP improves inflamed endothelial-monocyte adhesion via a PPARδ/IL-10-dependent pathway. The current study provides in vitro evidence for a therapeutic approach for treating atherosclerosis.
卡马替尼（CAP）是一种已被用于治疗成人非小细胞肺癌（NSCLC）的药物。目前，人们发现它对脂肪细胞中骨骼肌胰岛素信号转导、炎症和脂肪生成具有新的作用，这为药物重新定位提供了新的视角。然而，卡马替尼对 LPS 介导的人脐静脉内皮细胞（HUVEC）和 THP-1 单核细胞之间相互作用的影响尚未被研究。
用 LPS 和 CAP 处理 HUVEC 和 THP-1 单核细胞。使用 Western blot 测定蛋白表达水平。用小干扰（si）RNA 转染进行靶蛋白敲低。用绿色荧光染料测定 HUVEC 和 THP-1 细胞之间的相互作用。
本研究发现 CAP 治疗可改善 THP-1 单核细胞与 HUVEC 之间的细胞黏附以及粘附分子（如细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）和 E-选择素）的表达。此外，CAP 治疗可阻止 LPS 诱导的炎症标志物（如 NFκB 和 IκB 以及从 HUVEC 和 THP-1 单核细胞释放的 TNFα 和单核细胞趋化蛋白-1（MCP-1））的磷酸化。CAP 处理可增强 PPARδ 和 IL-10 的表达。用 siRNA 抑制 PPARδ 和 IL-10 可消除 CAP 对 HUVEC 和 THP-1 细胞之间细胞相互作用和炎症反应的影响。此外，PPARδ siRNA 可减轻 CAP 介导的 IL-10 表达诱导。
这些发现表明 CAP 通过 PPARδ/IL-10 依赖性途径改善了炎症诱导的内皮-单核细胞黏附。本研究为治疗动脉粥样硬化提供了体外治疗方法的证据。
