Regulation of interleukin-8 expression by HMG-CoA reductase inhibitors in human vascular smooth muscle cells.
Interleukin-8 (IL-8) is a potent chemotactic factor that has been implicated in atherogenesis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid mechanisms such as inhibition of cytokine expression. In this study, we investigated the effects of statins on IL-8 synthesis in human vascular smooth muscle cells (VSMCs). Addition of angiotensin II (Ang II) increased IL-8 production in VSMCs in a time (0-24 h)- and dose (10(-8)-10(-6) mol/l)-dependent manner with increased IL-8 mRNA accumulation. The Ang II type 1 receptor (AT1R) antagonist candesartan, but not the Ang II type 2 receptor (AT2R) antagonist PD123319, significantly blocked Ang II-induced IL-8 production. Addition of fluvastatin decreased the basal and Ang II-induced IL-8 production in VSMCs in a dose (10(-8)-10(-5) mol/l)-dependent manner with a decrease in IL-8 mRNA accumulation. The effect of fluvastatin on IL-8 production was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene or farnesyl-pyrophosphate. Lipophilic cerivastatin also significantly decreased IL-8 production, while hydrophilic pravastatin showed no effect on IL-8 levels. In conclusion, we demonstrated for the first time that Ang II increased IL-8 production and fluvastatin decreased the basal and Ang II-induced IL-8 production in human VSMCs. These findings suggested that Ang II may exacerbate atherosclerosis through induction of IL-8 in VSMCs, while statins may exert therapeutic effects by modulating IL-8 synthesis in patients with atherosclerotic disease.
Ito
Takayuki
T
Division of Cardiovascular Medicine, Jichi Medical School, Minamikawachi-Machi, Tochigi 329-0498, Japan.
Ikeda
Uichi
U
Yamamoto
Keiji
K
Shimada
Kazuyuki
K
D000704:Analysis of Variance; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000032:analysis / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011336:Probability; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis*; D012680:Sensitivity and Specificity
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D000077340:Fluvastatin; C086276:cerivastatin; D017035:Pravastatin