TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase.
TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase.
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DOI：
10.1038/hr.2015.55
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Matsuzaki M
中科院分区：
文献类型：
--
作者：
Nakashima T;Umemoto S;Yoshimura K;Matsuda S;Itoh S;Murata T;Fukai T;Matsuzaki M
Toll样受体4（TLR4）和血管紧张素II（AngII）通过产生活性氧（ROS）诱导血管重塑。AngII还显示出增加抗氧化酶细胞外超氧化物歧化酶（ecSOD）。然而，TLR4在Ang II诱导的ROS产生、血管重塑和高血压中的作用仍不清楚。缺乏TLR4功能的小鼠显示出对慢性AngII输注的血管重塑的显著抑制，对血压没有影响。ROS水平和NADPH氧化酶活性的增加，在响应血管紧张素II输注显着钝化TLR4缺陷小鼠。在用亚降压剂量的AT1受体拮抗剂厄贝沙坦治疗的野生型（WT）小鼠中观察到类似的效果，其对TLR4缺陷小鼠没有影响。有趣的是，AngII输注诱导的ecSOD活性和表达的增加在TLR4缺陷小鼠中与WT小鼠相比有所增强，而促炎趋化因子MCP-1的表达降低。重要的是，AngII诱导的血管重塑与NADPH氧化酶活性、ROS水平和MCP-1表达水平呈正相关。值得注意的是，慢性去甲肾上腺素输注（其升高血压而不增加ROS产生）在WT小鼠中不诱导显著的血管重塑。总之，这些发现表明，ROS升高是加速血管重塑所必需的，但不是该模型中的高血压效应所必需的。我们证明，TLR4通过抑制抗氧化酶ecSOD的表达和活性，以及通过激活NADPH氧化酶，增强炎症，促进血管重塑的进展，在调节AngII诱导的血管ROS水平中起着关键作用。
Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.
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影响因子：
3
作者：
Kawahara, S;Umemoto, S;Matsuzaki, M
通讯作者：
Matsuzaki, M
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
--
作者：
Ji, Yuanyuan;Liu, Juntian;Liu, Na
通讯作者：
Liu, Na
DOI：
10.1152/ajprenal.1997.272.4.f515
发表时间：
1997-04-01
影响因子：
4.2
作者：
Oliverio, MI;Best, CF;Coffman, TM
通讯作者：
Coffman, TM
DOI：
10.1073/pnas.0403249101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Michelsen, KS;Wong, MH;Arditi, M
通讯作者：
Arditi, M