| First Author | Hu C | Year | 2008 |
| Journal | J Biol Chem | Volume | 283 |
| Issue | 16 | Pages | 10226-31 |
| PubMed ID | 18182394 | Mgi Jnum | J:136529 |
| Mgi Id | MGI:3796454 | Doi | 10.1074/jbc.M708820200 |
| Citation | Hu C, et al. (2008) Regulation of TGFbeta1-mediated collagen formation by LOX-1: studies based on forced overexpression of TGFbeta1 in wild-type and lox-1 knock-out mouse cardiac fibroblasts. J Biol Chem 283(16):10226-31 |
| abstractText | Transforming growth factor beta(1) (TGFbeta(1)) activation leads to tissue fibrosis. Here, we report on the role of LOX-1, a lectin-like 52-kDa receptor for oxidized low density lipoprotein, in TGFbeta(1)-mediated collagen expression and underlying signaling in mouse cardiac fibroblasts. TGFbeta(1) was overexpressed in wild-type (WT) and LOX-1 knock-out mouse cardiac fibroblasts by transfection with adeno-associated virus type 2 vector carrying the active TGFbeta(1) moiety (AAV/TGFbeta (ACT)(1)). Transfection of WT mouse cardiac fibroblasts with AAV/TGFbeta (ACT)(1) markedly enhanced the expression of NADPH oxidases (p22(phox), p47(phox), and gp91(phox) subunits) and LOX-1, formation of reactive oxygen species, and collagen synthesis, concomitant with an increase in the activation of p38 and p44/42 mitogen-activated protein kinases (MAPK). The TGFbeta(1)-mediated increase in collagen synthesis was markedly attenuated in the LOX-1 knock-out mouse cardiac fibroblasts as well as in WT mouse cardiac fibroblasts treated with a specific anti-LOX-1 antibody. Treatment with anti-LOX-1 antibody also reduced NADPH oxidase expression and MAPK activation. The NADPH oxidase inhibitors and gp91phox small interfering RNA reduced LOX-1 expression, MAPK activation, and collagen formation. The p38 MAPK inhibitors as well as the p44/42 MAPK inhibitors reduced collagen formation without affecting LOX-1 expression in cardiac fibroblasts. These observations suggest that collagen synthesis in cardiac fibroblasts involves a facilitative interaction between TGFbeta(1)-NADPH oxidase and LOX-1. Further, the activation of MAPK pathway appears to be downstream of TGFbeta(1)-reactive oxygen species-LOX-1 cascade. |
