Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

被引：11
作者：
Liu, Xin-Hua [1 ]
Wang, Xi-Ling [1 ]
Xin, Hong [1 ]
Wu, Dan [1 ]
Xin, Xiao-Ming [1 ]
Miao, Lei [1 ]
Zhang, Qiu-Yan [1 ]
Zhou, Yang [2 ]
Liu, Qian [2 ]
Zhang, Qian [2 ]
Zhu, Yi-Zhun [1 ]
机构：
[1] Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai Key Lab Bioact Small Mol, Shanghai 200433, Peoples R China
[2] Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China
来源：
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY | 2015年 / 36卷 / 04期
基金：
中国国家自然科学基金;
关键词：
Sodium 9-acetoxyltanshinone IIA sulfonate; Inflammation; Heme oxygenase-1; Macrophage; Nuclear factor erythroid 2-related factor 2; NF-KAPPA-B; TANSHINONE IIA; SIGNALING PATHWAY; VASCULAR INFLAMMATION; CELLS INVOLVEMENT; IN-VITRO; LIPOPOLYSACCHARIDE; ACTIVATION; EXPRESSION; MONOXIDE;
D O I：
10.1159/000430299
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Background/Aim: Sodium 9-acetoxyltanshinone IIA sulfonate (ZY-1A4), a novel compound derived from sodium 9-hydroxyltanshinone IIA sulfonate, was synthesized with potential biological activities. This study aimed to explore the effects of ZY-1A4 on lipopolysaccharide (LPS)-triggered inflammatory response and the underlying mechanisms. Methods: Activation of RAW264.7 macrophages was induced by LPS. The effects of ZY-1A4 on inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, nuclear factor-kappa B (NF-kappa B) activation, heme oxygenase-1 (HO-1) expression, and nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway were evaluated to elucidate its underlying mechanisms on inflammatory responses. Results: ZY-1A4 concentration-dependently reduced iNOS expression and NO production, and inhibited c-Jun-N-terminal kinase 1/2 (JNK1/2) phosphorylation and NF-kappa B activation in LPS-stimulated macrophages. In addition, ZY-1A4 concentration-and time-dependently induced HO-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of Nrf2, while the effect of ZY-1A4 was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Intriguingly, pharmacological inactivation of HO-1 with zinc protoporphyrin IX reversed anti-inflammatory effect of ZY-1A4, but the anti-inflammatory effect of ZY-1A4 was largely mimicked by HO-1 by-products carbon monoxide and bilirubin. Furthermore, the inhibitory effect of ZY-1A4 on LPS-induced iNOS expression and NO release was abolished by HO-1 siRNA or LY294002. Conclusion: Our results demonstrated that ZY-1A4 suppressed LPS-induced iNOS expression and NO generation via modulation of NF-kappa B activation and HO-1 expression. This new finding might shed light to the prevention and therapy of cardiovascular diseases. Copyright (C) 2015 S. Karger AG, Basel
引用
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页码：1316 / 1330
页数：15
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