Chronic activation of AMP-activated protein kinase prevents 20-hydroxyeicosatetraenoic acid-induced endothelial dysfunction.
Chronic activation of AMP-activated protein kinase prevents 20-hydroxyeicosatetraenoic acid-induced endothelial dysfunction.
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AMP 激活蛋白激酶的慢性激活可防止 20-羟基二十碳四烯酸诱导的内皮功能障碍。
DOI：
10.1111/j.1440-1681.2011.05509.x
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发表时间：
2011-05
影响因子：
2.9
通讯作者：
Keaney JF Jr
中科院分区：
文献类型：
--
作者：
Ward NC;Chen K;Li C;Croft KD;Keaney JF Jr
20-羟基二十碳四烯酸（20-HETE）是一种有效的血管收缩剂，参与血管功能障碍和血压调节。研究表明20-HETE和内皮功能障碍之间存在很强的相关性，但其信号传导机制在很大程度上尚不清楚。因此，我们试图研究20-HETE对内皮型一氧化氮合酶（eNOS）和热休克蛋白90（Hsp 90）协会的影响。20-HETE分别显着增强苯肾上腺素和乙酰胆碱对小鼠主动脉环的收缩并抑制其舒张（与对照环相比p=0.05）。在具有慢性AMP活化蛋白激酶（AMPK）活化的小鼠中，这保护免受20-HETE的负面作用（p<0.05）。用20-HETE处理的细胞中eNOS的免疫沉淀显示基础和血管内皮生长因子（VEGF）刺激的Hsp 90与eNOS的结合减少（p<0.05）。用AICAR（AMPK的慢性激活剂）预处理细胞防止了20-HETE处理后Hsp 90与eNOS结合的丧失。用20-HETE处理24小时诱导eNOS磷酸化的增加，在急性处理（30分钟）后未观察到。这伴随着Akt磷酸化的瞬时变化。20-HETE损害eNOS-Hsp 90结合，其可通过AMPK的慢性激活逆转。这提供了在具有升高的20-HETE水平的疾病（例如高血压）中降低的NO生物活性和内皮功能障碍的机制。
20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor involved in vascular dysfunction and blood pressure regulation. Studies have revealed strong associations between 20-HETE and endothelial dysfunction however the signalling mechanisms are largely unknown. Therefore we sought to investigate the effect of 20-HETE on endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (Hsp90) association. 20-HETE significantly enhanced the constriction and inhibited the relaxation of mouse aortic rings in response to phenylephrine and acetylcholine, respectively (p=0.05 versus control ring). In mice with chronic AMP-activated protein kinase (AMPK) activation this protected against the negative effects of 20-HETE (p<0.05). Immunoprecipitation of eNOS in cells treated with 20-HETE revealed a decrease in basal and vascular endothelial growth factor (VEGF) stimulated Hsp90 association with eNOS (p<0.05). Pre-treatment of the cells with AICAR (a chronic activator of AMPK) prevented the loss of Hsp90 association with eNOS following 20-HETE treatment. Treatment with 20-HETE for 24h induces an increase in eNOS phosphorylation, not observed following acute treatment (30mins). This was accompanied by transient changes in Akt phosphorylation. 20-HETE impairs eNOS-Hsp90 association which can be reversed via chronic activation of AMPK. This provides a mechanism for reduced NO bioactivity and endothelial dysfunction in diseases with elevated 20-HETE levels, such as hypertension.
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影响因子：
37.8
作者：
Förstermann, U;Münzel, T
通讯作者：
Münzel, T
影响因子：
37.8
作者：
Schulz, E;Anter, E;Keaney, JF
通讯作者：
Keaney, JF
影响因子：
7.4
作者：
Ward, NC;Puddey, IB;Croft, KD
通讯作者：
Croft, KD
影响因子：
4.8
作者：
Takahashi, S;Mendelsohn, ME
通讯作者：
Mendelsohn, ME
影响因子：
4
作者：
Sessa, WC
通讯作者：
Sessa, WC