In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation
In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation
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DOI：
10.1038/82176
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发表时间：
2000-12-01
期刊：
影响因子：
82.9
通讯作者：
Sessa, WC
中科院分区：
文献类型：
--
作者：
Bucci, M;Gratton, JP;Sessa, WC
小窝蛋白-1是小窝的主要外壳蛋白，它通过与关键的信号分子结合在一起，作为信号转导的调节因子。然而，Cavorin-1在信号调节中的生理重要性一直很难与其在小窝组装、跨细胞和胆固醇运输方面的传统功能区分开来。为了直接解决小窝蛋白支架结构域在体内的重要性，我们合成了一个与小窝蛋白-1支架结构域(氨基酸82-101)融合的嵌合肽。嵌合肽被有效地带入血管和内皮细胞，分别选择性地抑制乙酰胆碱(Ach)诱导的血管扩张和一氧化氮(NO)的产生，更重要的是，小鼠全身应用嵌合肽可以抑制急性炎症和血管渗漏，其程度与糖皮质激素或内皮型一氧化氮合酶(ENOS)抑制剂相同。这些数据表明，小窝蛋白-1支架结构域可以选择性地调节内皮细胞内eNOS的信号转导，该结构域的小分子模拟可能提供一种新的治疗途径。
Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its "scaffolding domain" to key signaling molecules. However, the physiological importance of caveorin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82-101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetyl-choline (Ach)-induced vasodilation and nitric oxide (NO) production, respectively, More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach.