Anesthesiology Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 Guangdong, China.
Operating Centre of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 Guangdong, China.
Mediators Inflamm. 2020 Feb 10;2020:7039854. doi: 10.1155/2020/7039854. eCollection 2020.
Current studies have identified the multifaceted protective functions of dexmedetomidine on multiple organs. For the first time, we clarify effects of dexmedetomidine on monocyte-endothelial adherence and whether its underlying mechanism is relative to connexin43 (Cx43), a key factor regulating monocyte-endothelial adherence. U937 monocytes and human umbilical vein endothelial cells (HUVECs) were used to explore monocyte-endothelial adherence. Two special siRNAs were designed to knock down Cx43 expression on HUVECs. U937-HUVEC adhesion, adhesion-related molecules, and the activation of the MAPK (p-ERK1/2, p-p38, and p-JNK1/2) signaling pathway were detected. Dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), was given as pretreatments to HUVECs. Its effects on Cx43 and U937-HUVEC adhesion were also investigated. The results show that inhibiting Cx43 on HUVECs could attenuate the contents of MCP-1, soluble ICAM-1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and the nonprocessed variants of the adhesion molecules ICAM-1 and VCAM-1 and ultimately result in U937-HUVEC adhesion decrease. Meanwhile, the activation of MAPKs was also inhibited. U0126 (inhibiting p-ERK1/2) and SB202190 (inhibiting p38) decreased the contents of MCP-1, sICAM-1, and sVCAM-1, but SP600125 (inhibiting p-JNK1/2) had none of these effects. ICAM-1 and VCAM-1 could be regulated in a similar way. Dexmedetomidine pretreatment inhibited Cx43 on HUVECs, the activation of MAPKs, and U937-HUVEC adhesion. Therefore, we conclude that dexmedetomidine attenuates U937-HUVEC adhesion via inhibiting Cx43 on HUVECs modulating the activation of MAPK signaling pathways.
目前的研究已经确定了右美托咪定对多种器官的多方面保护作用。我们首次阐明了右美托咪定对单核细胞-内皮细胞黏附的影响，以及其潜在机制是否与连接蛋白 43（Cx43）有关，Cx43 是调节单核细胞-内皮细胞黏附的关键因素。使用 U937 单核细胞和人脐静脉内皮细胞（HUVEC）来探索单核细胞-内皮细胞黏附。设计了两种特殊的 siRNA 来敲低 HUVEC 上的 Cx43 表达。检测 U937-HUVEC 黏附、黏附相关分子以及 MAPK（p-ERK1/2、p-p38 和 p-JNK1/2）信号通路的激活。将右美托咪定以其临床相关浓度（0.1 nM 和 1 nM）预处理 HUVEC，研究其对 Cx43 和 U937-HUVEC 黏附的影响。结果表明，抑制 HUVEC 上的 Cx43 可降低单核细胞趋化蛋白 1（MCP-1）、可溶性细胞间黏附分子 1（sICAM-1）、可溶性血管细胞黏附分子 1（sVCAM-1）以及黏附分子 ICAM-1 和 VCAM-1 的未加工变体的含量，并最终导致 U937-HUVEC 黏附减少。同时，MAPKs 的激活也受到抑制。U0126（抑制 p-ERK1/2）和 SB202190（抑制 p38）降低了 MCP-1、sICAM-1 和 sVCAM-1 的含量，但 SP600125（抑制 p-JNK1/2）没有这些作用。ICAM-1 和 VCAM-1 可以以类似的方式进行调节。右美托咪定预处理抑制 HUVEC 上的 Cx43、MAPKs 的激活以及 U937-HUVEC 黏附。因此，我们得出结论，右美托咪定通过抑制 HUVEC 上的 Cx43 调节 MAPK 信号通路的激活来减轻 U937-HUVEC 黏附。
