α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While alpha 1- and beta-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about alpha 2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of alpha 2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the alpha 2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of alpha 2a-, alpha 2b-, and alpha 2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only alpha 2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in alpha-smooth muscle actin, transforming growth factor-beta and alpha 2a-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-beta. In conclusion, we suggest that the alpha 2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.