金雀异黄素通过内质网 p38/ERK1/2-PPARγ-NF-κB 信号通路抑制血管平滑肌细胞中 Ang II 诱导的 CRP 和 MMP-9 的产生。
Genistein inhibits Ang II-induced CRP and MMP-9 generations via the ER-p38/ERK1/2-PPARγ-NF-κB signaling pathway in rat vascular smooth muscle cells.
机构信息
Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an 710061, People's Republic of China; Department of Pharmacy, The First Affiliated Hospital of Xi'an Medical University, Xi'an 710077, People's Republic of China; Hospital Management Institute of Xi'an Medical University, Xi'an 710077, People's Republic of China.
Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an 710061, People's Republic of China.
出版信息
Life Sci. 2019 Jan 1;216:140-146. doi: 10.1016/j.lfs.2018.11.036. Epub 2018 Nov 16.
AIMS
C-reactive protein (CRP) and matrix metalloproteinase (MMP)-9 are involved in the inflammation of atherosclerosis lesions. Genistein (Gen) has been demonstrated to exert beneficial effect on the cardiovascular system. However, it remains unclear whether Gen produces anti-inflammatory effect in vascular smooth muscle cells (VSMCs). Therefore, we investigated the effects of Gen on CRP and MMP-9 expressions induced by angiotensin (Ang) II in VSMCs and the related molecular mechanism.
MAIN METHODS
Rat VSMCs were cultured, and Ang II was used as a stimulant for CRP and MMP-9 expressions. CRP level was measured by ELISA. The mRNA and protein expressions of related indexes were identified by reverse transcription-polymerase chain reaction and western blot, respectively.
KEY FINDINGS
Gen inhibited Ang II-stimulated CRP and MMP-9 mRNA and protein expressions in concentration- and time-dependent manners. Additionally, Gen ameliorated Ang II-induced p-ERK1/2, p-p38 and NF-κB expressions, antagonized Ang II-downregulated peroxisome proliferation-activated receptor (PPAR) γ and estrogen receptor (ER) β expressions. After treating the VSMCs with GW9662 or ICI182780 in Gen treated groups, inhibitory effect of Gen on CRP and MMP-9 expressions were antagonized in Ang II-stimulated VSMCs. The treatment of VSMCs with ICI182780 abolished downregulations of p-p38/p-ERK1/2, and antagonized upregulation of PPARγ by Gen in Ang II-stimulated VSMCs. Moreover, the inhibitory effect of Gen on Ang II-stimulated NF-κB expression was abolished after preincubation of VSMCs with GW9662 in Gen treated groups.
SIGNIFICANCE
Gen exerts anti-inflammatory property via the ER-p38/ERK1/2-PPARγ-NF-κB-CRP/MMP-9 signal pathway in Ang II-stimulated VSMCs.
目的
C-反应蛋白（CRP）和基质金属蛋白酶（MMP）-9 参与动脉粥样硬化病变的炎症反应。染料木黄酮（Gen）已被证明对心血管系统有有益的影响。然而，Gen 是否在血管平滑肌细胞（VSMCs）中产生抗炎作用仍不清楚。因此，我们研究了 Gen 对血管紧张素（Ang）II 诱导的 VSMCs 中 CRP 和 MMP-9 表达的影响及其相关分子机制。
主要方法
培养大鼠 VSMCs，用 Ang II 刺激 CRP 和 MMP-9 表达。通过 ELISA 测定 CRP 水平。通过逆转录-聚合酶链反应和 Western blot 分别鉴定相关指标的 mRNA 和蛋白表达。
主要发现
Gen 呈浓度和时间依赖性抑制 Ang II 刺激的 CRP 和 MMP-9 mRNA 和蛋白表达。此外，Gen 改善了 Ang II 诱导的 p-ERK1/2、p-p38 和 NF-κB 表达，拮抗了 Ang II 下调的过氧化物酶体增殖物激活受体（PPAR）γ和雌激素受体（ER）β表达。在 Gen 处理组的 VSMCs 中用 GW9662 或 ICI182780 处理后，Gen 对 CRP 和 MMP-9 表达的抑制作用在 Ang II 刺激的 VSMCs 中被拮抗。ICI182780 处理 VSMCs 消除了 Gen 对 Ang II 刺激的 p-p38/p-ERK1/2 的下调，并拮抗了 Gen 对 Ang II 刺激的 VSMCs 中 PPARγ的上调。此外，GW9662 预处理消除了 Gen 对 Ang II 刺激的 NF-κB 表达的抑制作用。
意义
Gen 通过 ER-p38/ERK1/2-PPARγ-NF-κB-CRP/MMP-9 信号通路在 Ang II 刺激的 VSMCs 中发挥抗炎作用。
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