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Selective α1B- and α1D-adrenoceptor antagonists suppress noradrenaline-induced activation, proliferation and ECM secretion of rat hepatic stellate cells in vitro

   
@article{APS4481,
	author = {Ting-ting Liu and Ti-long Ding and Yong Ma and Wei Wei},
	title = {Selective α 1B - and α 1D -adrenoceptor antagonists suppress noradrenaline-induced activation, proliferation and ECM secretion of rat hepatic stellate cells  in vitro },
	journal = {Acta Pharmacologica Sinica},
	volume = {35},
	number = {11},
	year = {2016},
	keywords = {},
	abstract = {Ting-ting LIU1, 2, Ti-long DING2, Yong MA1, 2, *, Wei WEI1, *
1Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China; 2Department of Liver Diseases, 123th Hospital of PLA of China, Bengbu 233015, China
 
Aim: To explore the effects of noradrenaline (NA) on hepatic stellate cells (HSCs) in vitro and to determine the adrenoceptor (AR) subtypes and underlying mechanisms.
Methods: The distribution and expressions of α1A-, α1B-, and α1D-ARs in HSC-T6 cells were analyzed using immunocytochemistry and RT-PCR. Cell proliferation was evaluated with MTT assay. The expression of HSC activation factors [transforming factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA)], extracellular matrix (ECM) secretion factors [tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen-Ι (ColΙ)] and PKC-PI3K-AKT signaling components (PKC, PI3K, and AKT) in the cells were detected by Western blotting and RT-PCR.

Results: Both α1B- and α1D-AR were expressed in the membrane of HSC-T6 cells, whereas α1A-AR was not detected. Treatment of the cells with NA concentration-dependently increased cell proliferation (EC50=277 nmol/L), which was suppressed by the α1B-AR antagonist CEC or by the α1D-AR antagonist BMY7378. Furthermore, NA (0.001, 0.1, and 10 μmol/L) concentration-dependently increased the expression of TGF-β1, α-SMA, TIMP-1 and ColΙ, PKC and PI3K, and phosphorylation of AKT in HSC-T6 cells, which were suppressed by CEC or BMY7378, or by pertussis toxin (PT), RO-32-0432 (PKC antagonist), LY294002 (PI3K antagonist) or GSK690693 (AKT antagonist).

Conclusion: NA promotes HSC-T6 cell activation, proliferation and secretion of ECM in vitro via activation of Gα-coupled α1B-AR and α1D-AR and the PKC-PI3K-AKT signaling pathway.

 
Keywords: noradrenaline; hepatic fibrosis; hepatic stellate cell; α1-adrenoceptor; Gα; PKC; PI3K; AKT
 
This study was supported by the National Natural Science Foundation of China (No 81173075) and the Nanjing Military Medical Science and Technology Innovation Foundation of China (No 10MA037).
* To whom correspondence should be addressed.  
E-mail my4973766@163.com (Yong MA); wwei@ahmu.edu.cn (Wei WEI) 
Received 2014-04-03     Accepted 2014-07-07},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/4481}
}