CD38-mediated Ca2+ Signaling Contributes to Angiotensin II-induced Activation of Hepatic Stellate Cells: ATTENUATION OF HEPATIC FIBROSIS BY CD38 ABLATION* |
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Authors: | Seon-Young Kim Baik Hwan Cho Uh-Hyun Kim |
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Institution: | From the Departments of ‡Biochemistry and ;§Surgery and ;the ¶Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea |
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Abstract: | CD38 is a type II glycoprotein that is responsible for the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), Ca2+-mobilizing second messengers. The activation of hepatic stellate cells (HSCs) is a critical event in hepatic fibrosis because these cells are the main producers of extracellular matrix proteins in the liver. Recent evidence indicates that the renin-angiotensin system plays a major role in liver fibrosis. In this study, we showed that angiotensin II (Ang II) evoked long lasting Ca2+ rises and induced NAADP or cADPR productions via CD38 in HSCs. Inositol 1,4,5-trisphosphate as well as NAADP-induced initial Ca2+ transients were prerequisite for the production of cADPR, which was responsible for later sustained Ca2+ rises in the Ang II-treated HSCs. Ang II-mediated inositol 1,4,5-trisphosphate- and NAADP-stimulated Ca2+ signals cross-talked in a dependent manner with each other. We also demonstrated that CD38 plays an important role in Ang II-induced proliferation and overproduction of extracellular matrix proteins in HSCs, which were reduced by an antagonistic cADPR analog, 8-bromo-cADPR, or in CD38−/− HSCs. Moreover, we presented evidence to implicate CD38 in the bile duct ligation-induced liver fibrogenesis; infiltration of inflammatory cells and expressions of α-smooth muscle actin, transforming growth factor-β1, collagen αI(1), and fibronectin were reduced in CD38−/− mice compared with those in CD38+/+ mice. These results demonstrate that CD38-mediated Ca2+ signals contribute to liver fibrosis via HSCs activation, suggesting that intervention of CD38 activation may help prevent hepatic fibrosis. |
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Keywords: | Diseases G Proteins/Coupled Receptors (GPCR) Signal Transduction/Calcium CD38 Cyclic ADP-ribose (cADPR) Hepatic Fibrosis Hepatic Stellate Cells Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) |
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