α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin
by
Ute A. Schwinghammer 1, Magda M. Melkonyan 2, Lilit Hunanyan 2, Roman Tremmel 3
, Ralf Weiskirchen 4, Erawan Borkham-Kamphorst 4, Elke Schaeffeler 3, Torgom Seferyan 5, Wolfgang Mikulits 6, Konstantin Yenkoyan 7, Matthias Schwab 1,3,7,8 and Lusine Danielyan 1,*
Ute A. Schwinghammer 1, Magda M. Melkonyan 2, Lilit Hunanyan 2, Roman Tremmel 3, Ralf Weiskirchen 4, Erawan Borkham-Kamphorst 4, Elke Schaeffeler 3, Torgom Seferyan 5, Wolfgang Mikulits 6, Konstantin Yenkoyan 7, Matthias Schwab 1,3,7,8 and Lusine Danielyan 1,*
1
Department of Clinical Pharmacology, University Hospital of Tuebingen, 72076 Tuebingen, Germany
2
Department of Medical Chemistry, Yerevan State Medical University, 0025 Yerevan, Armenia
3
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany, and University of Tuebingen, 72074 Tuebingen, Germany
4
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany
5
H. Buniatian Institute of Biochemistry, National Academy of Sciences of the Republic of Armenia (NAS RA), 0014 Yerevan, Armenia
6
Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
7
Department of Biochemistry and Neuroscience Laboratory, Yerevan State Medical University, 0025 Yerevan, Armenia
8
Department of Biochemistry and Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 456; https://doi.org/10.3390/cells9020456
Received: 2 January 2020 / Revised: 6 February 2020 / Accepted: 13 February 2020 / Published: 18 February 2020
(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)
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.
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Keywords:
α2-adrenoceptors; norepinephrine; mesedin; hepatic stellate cells; sinusoidal endothelial cells; liver fibrosis; sinusoidal permeability
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Schwinghammer, U.A.; Melkonyan, M.M.; Hunanyan, L.; Tremmel, R.; Weiskirchen, R.; Borkham-Kamphorst, E.; Schaeffeler, E.; Seferyan, T.; Mikulits, W.; Yenkoyan, K.; Schwab, M.; Danielyan, L. α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin. Cells 2020, 9, 456.
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