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Background: Post-induction hypotension, a common complication after propofol-based induction regimen, is a life-threatening challenge for anesthesiologists especially when unexpected pre-induction hypertension characterized by angiotensin release and increased vascular tone was presented by the same patient. Gap junctions (GJs) composed of connexin 43 (Cx43) have been considered a key factor in regulating vascular contraction and dilation. We aimed to explore the role of Cx43-GJs during peri-induction blood pressure fluctuation and elucidate the underlying mechanisms., Methods: Human umbilical arterial smooth muscle cells (HUASMCs) were pretreated by short-term Angiotensin Ⅱ (Ang Ⅱ) with or without subsequent propofol treatment to simulate transient contraction and dilation of vascular smooth muscle cells during anesthesia induction. F-actin polymerization, a classic indicator of HUASMCs constriction, was determined by F-actin staining assay. Both the function and expression of Cx43-GJs during transient contraction and dilation of HUASMCs, and their potential regulation of downstream Ca 2+ /RhoA/LIMK2/Cofilin signaling pathway were explored via different targeting inhibitors and siRNAs., Results: Ang Ⅱ pretreatment significantly induced F-actin polymerization that indicate cell contraction, accompanied by enhanced GJs function on HUASMCs. With the inhibition of Cx43 GJs by the specific inhibitor, Gap26, and Cx43-siRNA, Ang Ⅱ-induced F-actin polymerization was reversed accompanied with the decrease of intracellular Ca 2+ mobility and the RhoA/LIMK2/Cofilin signaling pathway activity. We also noticed that propofol application could inhibit GJs function, the same as Gap26. Simultaneously, intracellular Ca 2+ mobility and RhoA/LIMK2/Cofilin signaling pathway activity on HUASMCs were both downregulated, finally resulting in downstream reduction of F-actin polymerization., Conclusion: The function of Cx43-GJs lies in the center of Ang Ⅱ-induced contraction of HUASMCs, which potentially regulates intracellular Ca 2+ mobility as well as RhoA/LIMK2/Cofilin signaling pathway activity. Propofol can reverse this effect induced by Ang Ⅱ through suppressing the function of Cx43-GJs., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague-Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

Introduction: Pregnancy-induced hypertension (PIH) is the most common serious complication of pregnancy, resulting in significant maternal and fetal morbidity and mortality. Vasospasm is the main pathogenesis of PIH, which leads to the hemodynamic changes and the injury of vascular endothelial cells. However, the underlying mechanism is still unclear. Monocyte-endothelial adhesion is always considered to be one of the most important indicators of vascular endothelial cell injury. Connexin43 (Cx43) plays an important part in monocyte-endothelial adhesion. Thus, we explored effects of Cx43 on cell adhesion in PIH-induced vascular endothelial cells injury., Methods: We obtained human umbilical vein endothelial cells (HUVECs) from patients with or without PIH. Different methods, such as inhibitors: oleamide and Gap26, or specific siRNA were used to alter Cx43 channels function or protein expression in normal or PIH-HUVECs. U937-HUVECs adhesion, adhesion molecules expression, such as VCAM-1 and ICAM-1, and the activity of PI3K/AKT/NF-κB signaling pathway were determined., Results: Monocyte-endothelial adhesion on PIH-HUVECs was much more obvious than that on normal HUVECs. Inhibition of Cx43 protein expression could attenuate cell adhesion significantly, however, function of Cx43 channels had no effects on it. Alternation of Cx43 protein expression on PIH-HUVECs mediated VCAM-1 and ICAM-1 expression via regulating the activity of PI3K/AKT/NF-κB signaling pathway., Conclusions: We firstly reported Cx43 protein expression on PIH-HUVECs was much higher than that on normal HUVECs. Elevation of Cx43 protein expression within the vasculature resulted in PI3K/AKT/NF-κB signaling pathway activation and VCAM-1 and ICAM-1 over-expression, which ultimately lead to monocyte-endothelial adhesion increase., (Copyright © 2019. Published by Elsevier Ltd.)

Monocyte-endothelial adhesion is considered to be the primary initiator of inflammatory vascular diseases, such as atherosclerosis. Connexin 43 (Cx43) has been reported to play an important part in this process, however, the underlying mechanisms are not fully understood. Intravenous anesthetics, propofol is commonly used in the perioperative period and in the intensive care unit, and considered to have good anti-inflammatory and antioxidant effects. Thus, we speculate that propofol could influence monocyte-endothelial adhesion, and explore whether its possible mechanism is relative with Cx43 expression in U937 monocytes influencing cell adhesion of U937 monocytes to human umbilical vein endothelial cells (HUVEC). Cx43-siRNAs or pc-DNA-Cx43 were used to alter Cx43 expression in U937 monocytes. Propofol was given as pretreatments to U937 monocytes. Then, cell adhesion, ZO-1, LFA-1, VLA-4, COX and MCP-1 were determined. PI3K/AKT/NF-κB signaling pathway was explored to clarify the possible mechanism. Alternation of Cx43 expression affects cell adhesion and adhesion molecules significantly, such as ZO-1, LFA-1, VLA-4, COX-2 and MCP-1, the mechanism of which is relative with Cx43 influencing the activation of PI3K/AKT/NF-κB signaling pathway. Preconditioning with propofol at its clinically relevant anesthesia concentration attenuates cell adhesion. Propofol not only decreases Cx43 expression in U937 monocytes, but also depresses the activation of PI3K/AKT/NF-κB signaling pathway. Modulation Cx43 expression in U937 monocytes could affect cell adhesion via regulating the activation of PI3K/AKT/NF-κB signaling pathway. Propofol attenuates cell adhesion via inhibiting Cx43 and its downstream signaling pathway of PI3K/AKT/NF-κB. [ABSTRACT FROM AUTHOR]