Simvastatin attenuates the additive effects of TNF-a and IL-18 on the connexin 43 up-regulation and over-proliferation of cultured aortic smooth muscle cells

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Title:	Simvastatin attenuates the additive effects of TNF-a and IL-18 on the connexin 43 up-regulation and over-proliferation of cultured aortic smooth muscle cells
Authors:	Yu-Chun Lin;Chiang-Hua Chiang;Li-Teh Chang;Cheuk-Kwan Sun;Steve Leu;Pei-Lin Shao;Ming-Chu Hsieh;Tzu-Hsien Tsai;Sarah Chua;Sheng-Ying Chung;Ying-Hsien Kao;Hon-Kan Yip
Keywords:	Aortic smooth muscle cells;Interleukin-18;Tumor necrosis factor-a;Connexin 43;PI3K/Akt signaling
Date:	2013
Issue Date:	2014-09-15T06:44:31Z (UTC)
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-a (TNF-a)-triggered Akt and MAPK signaling pathways. Simvastatin treatment alone reduced constitutive Cx43 levels and prevented the TNF-a-induced IL-18 up-regulation. Mechanistic investigation using kinase-specific inhibitors showed that simvastatin pretreatment attenuated TNF-a-elicited Akt and ERK1/2 phosphorylation, whereas PI3K and all MAPK activities were also implied in the additive effect of TNF-a and IL-18 on Cx43 up-regulation. Proliferation assay indicated that IL-18 stimulated SMC proliferation and synergized the TNF-a-stimulated cell proliferation. Likewise, simvastatin treatment suppressed the SMC over-proliferation induced not only by TNF-a alone, but also by simultaneous treatment with TNF-a and IL-18. The suppression of simvastatin in SMC proliferation was not mediated through mitochondrial related proapoptogenesis under both scenarios. In conclusion, simvastatin attenuates the additive effects of TNF-a 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.
Relation:	Cytokine 62 (2013) 341–351
Appears in Collections:	[Department of Nursing] Papers

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