Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins
Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins
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DOI：
10.1161/hh2201.100319
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发表时间：
2001-11-09
影响因子：
20.1
通讯作者：
Feron, O
中科院分区：
文献类型：
--
作者：
Brouet, A;Sonveaux, P;Feron, O
3-羟基-3-甲基戊二酰(HMG)-辅酶A还原酶抑制剂或他汀类药物通过增加一氧化氮（NO）的产生对内皮细胞产生直接的有益作用。在这里，我们研究了内皮NO合成酶（eNOS）的翻译后修饰是否可以解释他汀类药物的促血管生成作用。我们使用从心脏微血管、主动脉和脐静脉分离的内皮细胞（ECs），以及解剖的微血管和主动脉环，在重建的基底膜基质（Matrigel）上培养。他汀类药物治疗后评估管或毛细前形成，同时进行免疫印迹和免疫沉淀实验。阿托伐他汀刺激一氧化氮依赖性血管生成，独立于eNOS表达的变化，从分离和离体（血管来源）内皮细胞。我们发现，在宏观而非微血管内皮细胞中，阿托伐他汀通过降低小窝蛋白丰度及其与eNOS的抑制相互作用来稳定管的形成。我们还发现伴侣蛋白hsp90是他汀类药物促血管生成作用的关键靶点。利用hsp90功能抑制剂格尔达霉素和重组hsp90的过表达，我们证明了他汀类药物诱导的eNOS Ser1177磷酸化直接依赖于hsp90在eNOS复合体中招募Akt的能力。最后，我们发现他汀类药物促进了hsp90的酪氨酸磷酸化以及hsp90与Akt的直接相互作用，从而进一步增强了no依赖性血管生成过程。我们的研究为他汀类药物no介导的血管生成作用提供了新的机制见解，并强调了这些药物和其他hsp90和小泡蛋白丰富度调节剂在与动脉粥样硬化相关或不相关的疾病状态下促进新血管形成的潜力。
3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an increase in nitric oxide (NO) production. Here, we examined whether posttranslational modifications of the endothelial NO synthase (eNOS) could account for the proangiogenic effects of statins. We used endothelial cells (ECs) isolated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstituted basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immunoprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenesis from both isolated and outgrowing (vessel-derived) ECs, independently of changes in eNOS expression. We found that in macro- but not microvascular ECs, atorvastatin stabilized tube formation through a decrease in caveolin abundance and its inhibitory interaction with eNOS. We also identified the chaperone protein hsp90 as a key target for the proangiogenic effects of statins. Using geldanamycin, an inhibitor of hsp90 function, and overexpression of recombinant hsp90, we documented that the statin-induced phosphorylation of eNOS on Ser1177 was directly dependent on the ability of hsp90 to recruit Akt in the eNOS complex. Finally, we showed that statin promoted the tyrosine phosphorylation of hsp90 and the direct interaction of hsp90 with Akt, which further potentiated the NO-dependent angiogenic processes. Our study provides new mechanistic insights into the NO-mediated angiogenic effects of statins and underscores the potential of these drugs and other modulators of hsp90 and caveolin abundance to promote neovascularization in disease states associated or not with atherosclerosis.