Lercanidipine and labedipinedilol-A attenuate lipopolysaccharide/interferon-gamma-induced inflammation in rat vascular smooth muscle cells through inhibition of HMGB1 release and MMP-2, 9 activities

doi:10.1016/j.atherosclerosis.2012.12.005

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Title:	Lercanidipine and labedipinedilol-A attenuate lipopolysaccharide/interferon-gamma-induced inflammation in rat vascular smooth muscle cells through inhibition of HMGB1 release and MMP-2, 9 activities
Authors:	Yeh, Jwu-Lai Hsu, Jong-Hau Liang, Jyh-Chong Chen, Ing-Jun Liou, Shu-Fen
Contributors:	藥學系
Keywords:	Dihydropyridine Calcium Channel Blockers Vascular Smooth Muscle Cells Lipopolysaccharide/Interferon-Gamma
Date:	2013-02
Issue Date:	2014-05-26 10:47:28 (UTC+8)
Publisher:	Elsevier Ireland Ltd
Abstract:	Objective: Inflammation is an important molecular basis of atherosclerosis. Recent studies have shown that dihydropyridine calcium channel blockers (CCBs) can exert potent anti-inflammatory effects in models of vascular dysfunction. The purpose of the present study was to evaluate anti-inflammatory effects and mechanisms of lercanidipine and labedipinedilol-A, new generation dihydropyridine CCBs, in rat vascular smooth muscle cells (VSMCs) exposed to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma).Methods and results: MTT, Griess reagent, RT-PCR, ELISA, gelatin zymography, immunocytochemistry and Western blotting were employed. We found that lercanidipine and labedipinedilol-A attenuated production of NO, ROS and TNF-alpha from LPS/IFN-gamma-stimulated VSMCs. In addition, they both diminished the LPS/IFN-gamma-induced expression of iNOS protein and mRNA, with attenuation of HMGB1 cytosolic translocation and subsequent extracellular release. Furthermore, they down-regulated MMP-2/MMP-9 activities, whereas expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, was up-regulated. Finally, we found that lercanidipine and labedipinedilol-A inhibited the nuclear translocation of NF-kappa B and suppressed the phosphorylation of JNK, p38 MAPK and Akt.Conclusion: Lercanidipine and labedipinedilol-A can exert their anti-inflammatory effects through suppression of NO, ROS and TNF-alpha through down-regulation of iNOS, MMP-2/MMP-9, and HMGB1, with inhibition of signaling transduction of MAPKs, Akt/IkB-alpha and NF-kappa B pathways. These findings implicate a valuable role of new generation dihydropyridine CCBs lercanidipine and labedipinedilol-A for the treatment of inflammatory vascular diseases. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
Relation:	Atherosclerosis, v.226 n.2, pp.364-372
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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