High glucose enhances MMP-2 production in adventitial fibroblasts via Akt1-dependent NF-kappaB pathway |
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Authors: | Lee Seung Jin Bae Sun Sik Kim Koan Hoi Lee Won Suk Rhim Byung Yong Hong Ki Whan Kim Chi Dae |
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Affiliation: | 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. |
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Abstract: | 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. |
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Keywords: | HG, high glucose MMP, matrix metalloproteinase AF, adventitial fibroblasts ECM, extracellular matrix NF-κB, nuclear factor-kappa B AP-1, activator protein-1 EMSA, electrophoretic mobility shift assay ODN, oligodeoxynucleotides |
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