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: 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
• Journal: Cytokine (Cytokine) Vol. 62 Issue 3 Pg. 341-51 (Jun 2013) ISSN: 1096-0023 [Electronic] England
• PMID: 23618917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Azetidines
• Connexin 43
• Drug Combinations
• Ezetimibe, Simvastatin Drug Combination
• Interleukin-18
• Protein Kinase Inhibitors
• Tumor Necrosis Factor-alpha
• Simvastatin
• Phosphatidylinositol 3-Kinases

Topics

• Animals
• Aorta (pathology)
• Apoptosis (drug effects)
• Azetidines
• Cell Proliferation (drug effects)
• Cells, Cultured
• Connexin 43 (metabolism)
• Diet, High-Fat
• Down-Regulation (drug effects)
• Drug Combinations
• Drug Synergism
• Ezetimibe, Simvastatin Drug Combination
• Hypercholesterolemia (pathology)
• Interleukin-18 (pharmacology)
• Macrophages (drug effects)
• Myocytes, Smooth Muscle (drug effects, enzymology, metabolism, pathology)
• Neointima (pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rabbits
• Rats
• Signal Transduction (drug effects)
• Simvastatin (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation (drug effects)