α1AMP-activated protein kinase preserves endothelial function during chronic angiotensin II treatment by limiting Nox2 upregulation.
α1AMP-activated protein kinase preserves endothelial function during chronic angiotensin II treatment by limiting Nox2 upregulation.
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DOI：
10.1161/atvbaha.110.219543
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Schulz E
中科院分区：
文献类型：
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作者：
Schuhmacher S;Foretz M;Knorr M;Jansen T;Hortmann M;Wenzel P;Oelze M;Kleschyov AL;Daiber A;Keaney JF Jr;Wegener G;Lackner K;Münzel T;Viollet B;Schulz E
血管腺苷酸活化蛋白激酶（AMPK）除了具有广泛的代谢作用外，还能激活内皮细胞NO合成酶，促进血管新生，抑制内皮细胞凋亡。本研究旨在研究α1AMPK缺失在体内血管疾病中的作用。低降压剂量的ATII慢性输注导致轻度内皮功能障碍，在α1AMPK敲除小鼠中显著加重。出乎意料的是，这种内皮功能障碍与NO含量降低无关，因为通过血清亚硝酸盐或电子顺磁共振测量的NO水平甚至增加。然而，由于平行的超氧化物产生，在ATII处理的α1AMPK敲除小鼠中，NO在过氧亚硝酸盐的产生下被消耗，与NADPH氧化酶活化和Nox 2上调相关。由于Nox 2也是吞噬细胞NADPH氧化酶的一种成分，我们发现了几种促炎标志物的血管上调，包括诱导型NO合酶，血管细胞粘附分子-1和环氧合酶-2。与NADPH氧化酶抑制剂apocynin联合治疗能够预防血管炎症，并部分恢复α1AMPK敲除小鼠的内皮功能。我们的数据表明，在体内α 1 AMPK缺失导致Nox 2上调，导致内皮功能障碍和血管炎症。这暗示基础AMPK活性作为血管稳态中的保护性氧化还原调节元件。
Besides its well described metabolic effects, vascular AMP-activated protein kinase (AMPK) can activate endothelial NO synthase, promotes angiogenesis and limits endothelial cell apoptosis. The current study was designed to study the effects of α1AMPK deletion during vascular disease in vivo. Chronic ATII infusion at low subpressor doses caused a mild endothelial dysfunction that was significantly aggravated in α1AMPK knockout mice. Unexpectedly, this endothelial dysfunction was not associated with decreased NO-content, since NO-levels measured by serum nitrite or electron paramagnetic resonance were even increased. However, due to parallel superoxide production, NO was consumed under production of peroxynitrite in ATII-treated α1AMPK knockout mice, associated with NADPH oxidase activation and Nox2 upregulation. As Nox2 is also a component of phagocyte NADPH oxidases, we found a vascular upregulation of several pro-inflammatory markers including inducible NO synthase, vascular cell adhesion molecule-1 and cyclooxygenase-2. Co-treatment with the NADPH oxidase inhibitor apocynin was able to prevent vascular inflammation and also partially restored endothelial function in α1AMPK knockout mice. Our data indicate that in vivo α1AMPK deletion leads to Nox2 upregulation, resulting in endothelial dysfunction and vascular inflammation. This implicates basal AMPK activity as a protective, redox regulating element in vascular homeostasis.