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Cardiovasc Res:张莉莉等发现改善血管内膜增生新靶点

2012-8-3 作者:邹争春 李艳   来源:科技日报 我要评论1
Tags: 张莉莉    血管内膜增生    PPARγ    TLR4  
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近日,英国权威期刊《心血管研究》(Cardiovascular Research)发表了第三军医大学大坪医院野战外科研究所神经内科教授张莉莉课题组的研究发现,PPARγ(过氧化物酶体增生物激活受体-γ)通过抑制血管平滑肌细胞中TLR4(Toll样受体4)介导的炎症反应,改善血管内膜增生,为临床治疗血管增生性疾病提供了新思路。

内膜增生不仅是动脉粥样硬化的重要病理特征,也是血管重建手术失败的主要原因。抑制血管平滑肌细胞(VSMC)迁移和增殖是防止动脉内膜增生的一个重要策略。

PPARγ是一种核受体转录因子,通过调控各种参与葡萄糖和脂肪代谢的基因表达而调控糖尿病、动脉粥样硬化等疾病。张莉莉等研究发现,PPARγ激动剂罗格列酮可明显减轻导丝损伤引起的小鼠颈动脉内膜增生;在体外实验中上调PPARγ的表达可抑制培养的VSMC的增殖和迁移能力。

为深入探索PPARγ抑制VSMC迁移和增殖,防止动脉内膜增生的作用机制,课题组进一步对PPARγ调控的炎症反应检测发现,PPARγ和TLR4介导的炎症反应之间存在着交叉联系。激活PPARγ可显著降低导丝损伤后小鼠颈动脉中TLR4和炎症因子的表达;在体外实验中上调PPARγ表达也可抑制VSMC中TLR4和炎症因子的表达。而TLR4活化可显著减弱PPARγ对VSMC增殖和迁移的抑制作用。相对于正常的VSMC,PPARγ对TLR4缺陷VSMC的增殖和迁移能力未产生明显影响。上述结果显示TLR4缺乏可影响PPARγ调控VSMC增殖和迁移的作用,提示PPARγ抑制VSMC增殖和迁移的过程可能由TLR4信号通路介导。

doi:10.1093/cvr/cvr238
PMC:

PMID:

PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells

Li-Li Zhang*, Chang-Yue Gao, Chuan-Qin Fang, Yan-Jiang Wang, Dong Gao, Guo-En Yao, Jing Xiang, Jing-Zhou Wang and Jing-Cheng Li*

Aims Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to attenuate intimal hyperplasia. This study aimed to test the hypothesis that PPARγ inhibits intimal hyperplasia through suppressing Toll-like receptor 4 (TLR4)-mediated inflammation in vascular smooth muscle cells. Methods and results TLR4?/? mice on a C57BL/6J background were used. Increased TLR4 and pro-inflammatory cytokines were observed in wire-injury-induced carotid neointima and in platelet-derived growth factor (PDGF)-activated vascular smooth muscle cells. The TLR4 deficiency protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to lipopolysaccharide and PDGF. Rosiglitazone attenuated intimal hyperplasia. Overexpression of PPARγ suppressed PDGF-induced proliferation and migration and inhibited TLR4-mediated inflammation in vascular smooth muscle cells, while PPARγ silencing exerted the opposite effect. Lipopolysaccharide counteracted the inhibitory effect of PPARγ on PDGF-induced proliferation and migration. Eritoran suppressed the proliferation and migration induced by PDGF and PPARγ silencing. Vascular smooth muscle cells derived from TLR4?/? mice showed impaired proliferation and migration upon PDGF activation and displayed no response to PPARγ manipulation. Conclusion PPARγ inhibits vascular smooth muscle cell proliferation and migration by suppressing TLR4-mediated inflammation and ultimately attenuates intimal hyperplasia after carotid injury.



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所属期刊:CARDIOVASC RES 影响因子:5.878 期刊论坛:进入期刊论坛
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2017-5-9 8:10:48 回复

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