| First Author | Kim SY | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 1 | Pages | 576-82 |
| PubMed ID | 19910464 | Mgi Jnum | J:158284 |
| Mgi Id | MGI:4438506 | Doi | 10.1074/jbc.M109.076216 |
| Citation | Kim SY, et al. (2010) CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation. J Biol Chem 285(1):576-82 |
| abstractText | 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), Ca(2+)-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 Ca(2+) rises and induced NAADP or cADPR productions via CD38 in HSCs. Inositol 1,4,5-trisphosphate as well as NAADP-induced initial Ca(2+) transients were prerequisite for the production of cADPR, which was responsible for later sustained Ca(2+) rises in the Ang II-treated HSCs. Ang II-mediated inositol 1,4,5-trisphosphate- and NAADP-stimulated Ca(2+) 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 alpha-smooth muscle actin, transforming growth factor-beta1, collagen alphaI(1), and fibronectin were reduced in CD38(-/-) mice compared with those in CD38(+/+) mice. These results demonstrate that CD38-mediated Ca(2+) signals contribute to liver fibrosis via HSCs activation, suggesting that intervention of CD38 activation may help prevent hepatic fibrosis. |
