Involvement of reactive oxygen species and SP-1 in fibronectin production by oxidized LDL.
We examined the mechanisms responsible for the production of fibronectin induced by oxidized low-density lipoprotein (oxLDL) in rat mesangial cells. oxLDL accelerated the production of fibronectin with the preceding generation of reactive oxygen species (ROS). Pretreatment with N-acetylcysteine suppressed the oxLDL-induced fibronectin production as well as ROS generation. oxLDL also elicited the activation of SP-1, nuclear factor-kappaB, and cAMP response element-binding protein, but not activator protein-1. Among these activated transcription factors, N-acetylcysteine inhibited the activation of SP-1 only. 7-Ketocholesterol, an oxidized lipid in oxLDL particles, induced the production of fibronectin and the activation of SP-1, those which were suppressed by N-acetylcysteine. Furthermore, mithramycin A, an inhibitor of SP-1, also suppressed the oxLDL- and 7-ketocholesterol-stimulated production of fibronectin. These results suggest that oxLDL stimulates fibronectin production, at least in part, through the ROS-dependent activation of SP-1 in rat mesangial cells, and further that the ROS-dependent cellular responses may be elicited by 7-ketocholesterol.
Akiba
Satoshi
S
Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. akiba@mb.kyoto-phu.ac.jp
Chiba
Masahiro
M
Mukaida
Yuki
Y
Sato
Takashi
T
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005353:Fibronectins / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007653:Ketocholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*
D005353:Fibronectins; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C099252:oxidized low density lipoprotein; C003001:7-ketocholesterol; D000111:Acetylcysteine