Department of Clinical Pharmacology, University Hospital of Tuebingen, 72076 Tuebingen, Germany.
Department of Medical Chemistry, Yerevan State Medical University, 0025 Yerevan, Armenia.
Cells. 2020 Feb 18;9(2):456. doi: 10.3390/cells9020456.
The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-β and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-β. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.
去甲肾上腺素能系统被认为在肝纤维化的发病机制中起重要作用。虽然 α1-和 β-肾上腺素受体（AR）被认为参与了多种促纤维化作用，但对于 α2-AR 介导的作用及其在肝纤维化和肝硬化中的表达模式知之甚少。我们在两种实验性肝纤维化模型中研究了 α2-AR 的表达。我们进一步评估了 α2-AR 阻滞剂美司汀激活肝星状细胞（HSCs）和增加人肝窦内皮细胞（hLSECs）通透性的能力。与对照组相比，四氯化碳处理的小鼠中 α2a-、α2b-和 α2c-AR 亚型的 mRNA 均均匀上调，而在胆管结扎的小鼠中，只有 α2b-AR 对肝损伤有反应而增加。在小鼠 HSCs 中，美司汀导致 α-平滑肌肌动蛋白、转化生长因子-β和 α2a-AR 的表达减少，这通过 RT-qPCR、免疫细胞化学和 Western blot 分析得到证实。在 hLSEC 系中，检测到内皮型一氧化氮合酶的表达增加，同时转化生长因子-β的表达下调。总之，我们认为 α2-AR 阻断减轻了 HSCs 的激活，并可能在肝损伤期间增加肝窦的通透性。
