The novel function of advanced glycation end products in regulation of MMP-9 production.
The novel function of advanced glycation end products in regulation of MMP-9 production.
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DOI：
10.1016/j.jss.2010.04.027
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Zhang F;Banker G;Liu X;Suwanabol PA;Lengfeld J;Yamanouchi D;Kent KC;Liu B
晚期糖基化终末产物（AGEs）是蛋白质和多肽与醛糖接触后通过非酶促糖基化反应形成的，与年龄相关的心血管功能障碍的发病机制有关。我们以前的研究表明，在人类腹主动脉瘤（AAA）组织中AGE和AGE受体（AGE受体）水平显著升高。在AAA小鼠模型中，通过靶向基因缺失来抑制AGE信号传导显著减少了动脉瘤的发展。我们还发现AGE可能通过促进基质金属蛋白酶（MMP）-9的表达而刺激动脉瘤的形成。在这项研究中，我们研究了AGE这种新功能的分子机制。用AGE、TGF-β和MAPK抑制剂预处理鼠巨噬细胞系RAW 264.7。收集蛋白质用于Western印迹分析。收集培养上清液，通过明胶酶谱法测定MMP-9活性。我们发现AGE以剂量依赖的方式诱导巨噬细胞产生MMP-9。用TGF-β预处理可显著降低MMP-9的诱导作用。为了阐明潜在的分子机制，我们发现AGE增加了巨噬细胞中p44/42 ERK、p38、JNK和PI 3 K的磷酸化。AGE可诱导NF-κB p65亚基活化。ERK（UO 126）或p38（SB 203580）的抑制，而不是PI 3 K（LY 294002或wortmannin），阻断AGE诱导的MMP-9表达。与此相反，JNK（SP-600125）的抑制显着增强AGE对MMP-9的刺激作用。TGF-β还能抑制AGE诱导的NF-κB活性p65亚基的表达。我们的数据表明，AGE通过激活ERK、p38丝裂原活化蛋白和NF-κB诱导MMP-9，这是一条被TGF-β拮抗的途径。这一发现与之前报道的AGE在炎症中的功能相结合，表明抗AGE疗法可以有效预防人类AAA的发生和进展。
Advanced glycation end products (AGEs), formed from proteins and peptides by nonenzymatic glycoxidation after contact with aldose sugars, have been implicated in the pathogenesis of age-related cardiac and vascular dysfunction. Our previous study demonstrated significantly elevated levels of AGE and the receptor for AGE (RAGE) in human abdominal aortic aneurysm (AAA) tissues. Inhibition of AGE signaling by targeted gene deletion of RAGE markedly reduced the development of aneurysm in a mouse model of AAA. We also showed that AGE may stimulate aneurysm formation by promoting metalloproteinase (MMP)-9 expression. In this study, we investigated the molecular mechanism underlying this novel function of AGE. The murine macrophage cell line RAW 264.7 was pretreated with AGE, TGF-β, and MAPK inhibitors. The protein was collected for Western blot analysis. Culture supernatants were collected to determine MMP-9 activity by gelatin zymography. We found that AGE induced the production of MMP-9 in macrophages in a dose-dependent manner. This induction of MMP-9 was markedly diminished by pretreatment with TGF-β. To delineate the underlying molecular mechanism, we showed that AGE increased phosphorylation of p44/42 ERK, p38, JNK, and PI3K in macrophages. Moreover, AGE induced active p65 subunit of NF-κB. Inhibition of ERK (UO126) or p38 (SB203580), but not PI3K (LY294002 or wortmannin), blocked AGE-induced MMP-9 expression. In contrast, inhibition of JNK (SP-600125) significantly enhanced the stimulatory effect of AGE on MMP-9. Furthermore, TGF-β suppressed AGE-induced expression of the active p65 subunit of NF-κB. Our data indicate that AGE induces MMP-9 through activation of ERK, p38 mitogen-activated protein and NF-κB, a pathway that is antagonized by TGF-β. This finding in conjunction with previously reported AGE functions in inflammation suggests that anti-AGE therapies could be effective in the prevention of human AAA development and progression.
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影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT
影响因子：
2.4
作者：
Maddahi A;Chen Q;Edvinsson L
通讯作者：
Edvinsson L
影响因子：
37.8
作者：
Dai, JP;Losy, F;Allaire, E
通讯作者：
Allaire, E
DOI：
10.1161/01.atv.0000166601.49954.21
发表时间：
2005-07-01
影响因子：
8.7
作者：
Kazi, M;Zhu, CY;Eriksson, P
通讯作者：
Eriksson, P
影响因子：
12.8
作者：
Lee, Yun-Song;Tran, Huong Thi Lan;Van Ta, Quang
通讯作者：
Van Ta, Quang