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

Cells. 2020 Feb 18;9(2):456. doi: 10.3390/cells9020456.

Abstract

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.

Keywords: hepatic stellate cells; liver fibrosis; mesedin; norepinephrine; sinusoidal endothelial cells; sinusoidal permeability; α2-adrenoceptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Adrenergic alpha-2 Receptor Antagonists / therapeutic use*
  • Animals
  • Dioxanes / pharmacology
  • Dioxanes / therapeutic use*
  • Disease Models, Animal
  • Female
  • Humans
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / physiopathology
  • Mice
  • Receptors, Adrenergic, alpha-2 / genetics*
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use*

Substances

  • Adrenergic alpha-2 Receptor Antagonists
  • Dioxanes
  • Receptors, Adrenergic, alpha-2
  • Thiazoles
  • mesedin