title: Simvastatin attenuates the additive effects of TNF-α and IL-18 on the connexin 43 up-regulation and over-proliferation of cultured aortic smooth muscle cells.
abstract: Statin therapy is known to down-regulate inflammatory activities in atheromatous tissues of animals. The aims of this study were to examine the regulatory role of interleukin-18 (IL-18) in the connexin 43 (Cx43) and the proliferation of cultured aortic smooth muscle cells (SMCs) as well as to elucidate the underlying therapeutic mechanism of simvastatin. Vytorin therapy significantly alleviated high-cholesterol diet-induced hypercholesterolemia, suppressed neointimal hyperplasia, macrophage infiltration, and Cx43 and IL-18 expression in rabbit aortic walls. In vitro study using an aortic SMC line showed that IL-18 up-regulated constitutive Cx43 expression and potentiated tumor necrosis factor-α (TNF-α)-triggered Akt and MAPK signaling pathways. Simvastatin treatment alone reduced constitutive Cx43 levels and prevented the TNF-α-induced IL-18 up-regulation. Mechanistic investigation using kinase-specific inhibitors showed that simvastatin pretreatment attenuated TNF-α-elicited Akt and ERK1/2 phosphorylation, whereas PI3K and all MAPK activities were also implied in the additive effect of TNF-α and IL-18 on Cx43 up-regulation. Proliferation assay indicated that IL-18 stimulated SMC proliferation and synergized the TNF-α-stimulated cell proliferation. Likewise, simvastatin treatment suppressed the SMC over-proliferation induced not only by TNF-α alone, but also by simultaneous treatment with TNF-α and IL-18. The suppression of simvastatin in SMC proliferation was not mediated through mitochondrial related pro-apoptogenesis under both scenarios. In conclusion, simvastatin attenuates the additive effects of TNF-α and IL-18 on Cx43 up-regulation and over-proliferation of aortic SMCs, mainly through the blockade of Akt signaling pathway. These findings may fortify the rationale underlying the atheroprotective mechanism of statin therapy.
authors.affiliation: Department of Medical Research, E-DA Hospital, I-Shou University, Kaohsiung 824, Taiwan, ROC.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Chiang-Hua
authors.initials: CH
authors.lastname: Chiang
authors.forename: Li-Teh
authors.initials: LT
authors.lastname: Chang
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Pei-Lin
authors.initials: PL
authors.lastname: Shao
authors.forename: Ming-Chu
authors.initials: MC
authors.lastname: Hsieh
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D059305:Diet, High-Fat; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D000069499:Ezetimibe, Simvastatin Drug Combination; D006937:Hypercholesterolemia / Q000473:pathology; D020382:Interleukin-18 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D001384:Azetidines; D018031:Connexin 43; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D020382:Interleukin-18; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D019869:Phosphatidylinositol 3-Kinases