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

• Published in: Cytokine (Philadelphia, Pa.) Vol. 62; no. 3; pp. 341 - 351
• Main Authors: Lin, Yu-Chun, Chiang, Chiang-Hua, Chang, Li-Teh, Sun, Cheuk-Kwan, Leu, Steve, Shao, Pei-Lin, Hsieh, Ming-Chu, Tsai, Tzu-Hsien, Chua, Sarah, Chung, Sheng-Ying, Kao, Ying-Hsien, Yip, Hon-Kan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2013
• Subjects: additive effect; Animals; Aorta - pathology; Aortic smooth muscle cells; Apoptosis - drug effects; Azetidines; cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Connexin 43; Connexin 43 - metabolism; Diet, High-Fat; Down-Regulation - drug effects; Drug Combinations; Drug Synergism; Ezetimibe, Simvastatin Drug Combination; hypercholesterolemia; Hypercholesterolemia - pathology; hyperplasia; in vitro studies; Interleukin-18; Interleukin-18 - pharmacology; macrophages; Macrophages - drug effects; myocytes; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; necrosis; Neointima - pathology; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; phosphorylation; PI3K/Akt signaling; Protein Kinase Inhibitors - pharmacology; Rabbits; Rats; signal transduction; Signal Transduction - drug effects; Simvastatin - pharmacology; smooth muscle; therapeutics; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; Up-Regulation - drug effects; OCT; PI3K/Akt signaling; DAB; IHC; LDL-C; H&E; JNK; HCD; Tumor necrosis factor-α; Connexin 43; MAPK; SMCs; TC; HDL-C; IFN-γ; TG; PI3K; TNF-α; Aortic smooth muscle cells; Cx; IL-18; MEK1; Interleukin-18; ERK
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2013.04.003

•This study investigates the role of IL-18 in cultured aortal smooth muscle cells.•IL-18 up-regulates Cx43 expression in TNF-α dependent manner.•IL-18 additively enhances TNF-α-stimulated cell proliferation.•Statin reduces the additive effects via Akt blockade.•These findings fortify the atheroprotective mechanism of statin therapy. 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.