High glucose enhances MMP-2 production in adventitial fibroblasts via Akt1-dependent NF-kappaB pathway.
To understand the role of adventitial fibroblasts (AF) in diabetic vascular diseases, the importance of high glucose (HG, 25mM) on matrix metalloproteinase-2 (MMP-2) production in AF was determined. HG enhanced mRNA, protein and gelatinolytic activity of MMP-2. The enhanced MMP-2 activity was significantly attenuated not only by a PI3K inhibitor but also by an Akt inhibitor. These HG-induced MMP-2 responses were markedly reduced in Akt1-deficient (1KO) cells. The diminished HG-induced MMP-2 responses were completely restored by re-expression of Akt1. Both the reporter activity and electrophoretic mobility shift assay for activator protein-1 and nuclear factor-kappa B (NF-kappaB) were enhanced by HG, but NF-kappaB were not increased in 1KO cells. Furthermore, HG-induced MMP-2 responses were markedly suppressed by NF-kappaB decoy oligodeoxynucleotides. Based on these results, it is suggested that HG augments MMP-2 production via PI3K/Akt1/NF-kappaB pathway.
Lee
Seung Jin
SJ
Department of Pharmacology, BK21 Medical Science Education Center, College of Medicine, Pusan National University, 10 Ami-Dong 1-Ga, Seo-Gu, Busan 602-739, Republic of Korea.
Bae
Sun Sik
SS
Kim
Koan Hoi
KH
Lee
Won Suk
WS
Rhim
Byung Yong
BY
Hong
Ki Whan
KW
Kim
Chi Dae
CD
D000818:Animals; D003238:Connective Tissue / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D005947:Glucose / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D007527:Isoenzymes; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D005947:Glucose