Dexmedetomidine Attenuates LPS-Induced Monocyte-Endothelial Adherence via Inhibiting Cx43/PKC-α/NOX2/ROS Signaling Pathway in Monocytes

Abstract

Dexmedetomidine is widely used for sedating patients in operation rooms or intensive care units. Its protective functions against oxidative stress, inflammation reaction, and apoptosis have been widely reported. In present study, we explored the effects of dexmedetomidine on monocyte-endothelial adherence. We built lipopolysaccharide- (LPS-) induced monocyte-endothelial adherence models with U937 monocytes and human umbilical vein endothelial cells (HUVECs) and observed the effects of dexmedetomidine on U937-HUVEC adhesion. Specific siRNA was designed to knock-down Connexin43 (Cx43) expression in U937 monocytes. Gö6976, GSK2795039, and NAC were used to inhibit PKC-α, NOX2, and ROS, respectively. Then, we detected whether dexmedetomidine could downregulate Cx43 expression and its downstream PKC-α/NOX2/ROS signaling pathway activation and ultimately result in the decrease of U937-HUVEC adhesion. The results showed that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), could inhibit adhesion of molecule expression (VLA-4 and LFA-1) and U937-HUVEC adhesion. Simultaneously, it also attenuated Cx43 expression in U937 monocytes. With the downregulation of Cx43 expression, the activity of PKC-α and its related NOX2/ROS signaling pathway were reduced. Inhibiting PKC-α/NOX2/ROS signaling pathway with Gö6976, GSK2795039, and NAC, respectively, VLA-4, LFA-1 expression, and U937-HUVEC adhesion were all decreased. In summary, we concluded that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), decreased Cx43 expression in U937 monocytes and PKC-α associated with carboxyl-terminal domain of Cx43 protein. With the downregulation of PKC-α, the NOX2/ROS signaling pathway was inhibited, resulting in the decrease of VLA-4 and LFA-1 expression. Ultimately, U937-HUVEC adhesion was reduced.

Inhibition of Lipopolysaccharide-Induced Inflammatory and Oxidative Responses by Trans-cinnamaldehyde in C2C12 Myoblasts

“…And NOX1, which is highly expressed in skeletal muscle along with NOX2 and NOX4 [65,67], is increased by myostatin in C2C12 myoblasts [68], but its physiological role in regulating ROS production has not been well identified. In addition, the accumulated evidence supports that the activation of NOX1 and NOX2 can participate in LPS-induced inflammatory responses as well as ROS production [15,69,70]. Therefore, we investigated the effect of tCA on the protein levels of Nrf2 and HO-1 in LPS-stimulated C2C12 myoblasts, and found that tCA increased their levels in the presence of LPS.…”

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

“…The receptors for AMs, such as PSGL-1, β 2 integrin CD18, and α integrin CD11b, on neutrophils and microglia were also redox-dependent [ 122 , 123 ] and have been shown to participate in the initial movement of leukocytes into the ischemic region [ 124 ]. A recent report further showed that the NOX2/ROS signaling pathway can affect very late antigen-4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1) expression in monocytes [ 125 ]. This concludes that inhibiting NOX2/ROS signaling pathways might be an effective strategy to reduce monocyte-endothelial adherence.…”

A new side-effect of sufentanil: increased monocyte-endothelial adhesion

“…1 that ATP and ADO could reduce U937-HUVEC adhesion. Our previous reports had demonstrated that Cx43 over-expression on U937 monocytes increased U937-HUVEC adhesion via modulating PKC-α/NOX2/ROS signaling pathway [ 26 ]. Therefore, we speculated that the function of ATP reducing U937-HUVEC adhesion was reversed by Cx43 over-expression.…”