4-Hydroxynonenal enhances MMP-2 production in vascular smooth muscle cells via mitochondrial ROS-mediated activation of the Akt/NF-κB signaling pathways
4-Hydroxynonenal enhances MMP-2 production in vascular smooth muscle cells via mitochondrial ROS-mediated activation of the Akt/NF-κB signaling pathways
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DOI：
10.1016/j.freeradbiomed.2008.08.022
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发表时间：
2008-11-15
影响因子：
7.4
通讯作者：
Kim, Chi D.
中科院分区：
文献类型：
--
作者：
Lee, Seung J.;Seo, Kyo W.;Kim, Chi D.
4-羟基壬烯醛(HNE)在动脉粥样硬化病变处蓄积，但其在动脉粥样硬化进展中的作用尚不清楚。考虑到基质金属蛋白酶(MMPs)在斑块失稳中的作用，我们研究了HNE诱导血管平滑肌细胞(VSMC)产生MMP2的机制。HNE(1.0mM)刺激VSMC产生具有酶活性的MMP2，启动子活性增加，而启动子区域的核因子-kappaB结合位点突变则使其失去活性。转染Akt siRNA和PI3K/Akt抑制剂LY294002(10 PM)和SH-5(1.0 mU M)可显著抑制HNE诱导的NF-kappa B活性升高和随后产生的MMP2，Akt的磷酸化早在暴露于HNE的VSMC中5min就开始发生，并可通过抑制线粒体活性氧(ROS)而显著减弱。此外，在线粒体功能缺陷的VSMC和转染锰超氧化物歧化酶的细胞中，也证实了线粒体ROS对HNE诱导的Akt磷酸化和随后的MMP-2产生的影响。综上所述，这些结果表明，HNE通过线粒体ROS介导的Akt/NF-kappa B信号通路的激活，促进VSMC中MMP-2的产生。(C)2008 Elsevier Inc.预留所有灯光。
4-Hydroxynonenal (HNE) accumulates at atherosclerotic lesions, but its role in the progression of atherosclerosis is not clear. Considering the role of matrix metalloproteinases (MMP) in plaque destabilization, we investigated the mechanism by which HNE induces MMP production in vascular smooth Muscle Cells (VSMC) VSMC stimulated by HNE (1.0 mu M) produced enzymatically active MMP-2 with ail increased promoter activity, which was abolished by Mutation of the NF-kappa B binding site in the promoter region. The increased NF-kappa B activity with subsequent MMP-2 production by HNE was significantly attenuated by transfection with Akt siRNA as well as by pretreatment with the PI3K/Akt inhibitors LY294002 (10 PM) and SH-5 (1.0 mu M), The phosphorylation of Akt occurred as early as 5 min in VSMC exposed to HNE and was markedly attenuated by inhibition of mitochondrial reactive oxygen species (ROS). Furthermore the, impact of mitochondrial ROS on HNE-induced Akt phosphorylation with subsequent MMP-2 production was also demonstrated in mitochondrial function-deficient VSMC, as well as in cells transfected with manganese Superoxide dismutase. Taken together, these results Suggest that HNE enhances MMP-2 production in VSMC via mitochondrial ROS-mediated activation of the Akt/NF-kappa B signaling pathways. (C) 2008 Elsevier Inc. All Lights reserved.