title: Cilostazol inhibits interleukin-1-induced ADAM17 expression through cAMP independent signaling in vascular smooth muscle cells.
abstract: Increased A disintegrin and metalloprotease 17 (ADAM17) expression in vascular smooth muscle cells (VSMC) is implicated in the development of cardiovascular diseases including atherosclerosis and hypertension. Although cilostazol, type III phosphodiesterase (PDE III) inhibitor, has recently been found to inhibit VSMC proliferation, the mechanisms remain largely unclear. Here, we hypothesized that cilostazol regulates the ADAM17 expression in VSMC. In cultured VSMC, interleukin (IL)-1α and IL-1β significantly increased ADAM17 expression. MEK inhibitor U0126, NF-κB inhibitor BAY-11-7085, and siRNA targeting p65/RelA significantly inhibited IL-1α or IL-β-induced ADAM17 expression. Cilostazol significantly inhibited IL-1α or IL-1β-induced extracellular signal-regulated kinase (ERK) phosphorylation and ADAM17 expression. Unexpectedly, cilostamide, dibutryl cAMP, and forskolin did not affect IL-1-induced ADAM17 expression. Our results clearly demonstrated that IL-1 induces ADAM17 expression through ERK/NF-κB activation in VSMCs. Moreover, the inhibitory effects of cilostazol on IL-1-induced ADAM17 expression may be independent of the cAMP signaling pathway in VSMC. These novel findings may provide important clues to understanding the expression mechanisms of ADAM17 and the inhibitory mechanisms of cilostazol in VSMC proliferation.
authors.affiliation: Department of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takaguri
authors.affiliation: Department of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Department of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Imai
authors.affiliation: Department of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Satoh
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D034741:RNA, Small Interfering; D013777:Tetrazoles; D051996:Transcription Factor RelA; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D000072198:ADAM17 Protein; D000077407:Cilostazol
keywords: ADAM17; ERK; NF-κB; cilostazol; interleukin-1