Endothelial S100A1 modulates vascular function via nitric oxide
Endothelial S100A1 modulates vascular function via nitric oxide
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DOI：
10.1161/circresaha.108.172031
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发表时间：
2008-04-11
影响因子：
20.1
通讯作者：
Most, Patrick
中科院分区：
文献类型：
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作者：
Pleger, Sven T.;Harris, David M.;Most, Patrick
S100 A1是EF-手型的钙结合蛋白，已知其调节骨骼肌和心肌细胞中肌浆网的钙处理。最近，S100 A1已被证明在内皮细胞（EC）中表达。由于细胞内Ca 2+（[Ca 2 +]（i））瞬变可参与重要的EC功能和内皮NO合酶活性，我们试图研究内皮S100 A1对内皮和血管功能调节的影响。与野生型血管相比，S100 A1基因敲除小鼠（SKO）的胸主动脉对乙酰胆碱的舒张反应显着降低，而使用硝普钠的直接血管舒张反应则没有改变。S100 A1表达缺失导致的血管内皮功能障碍也可在体内被证实并转化为SKO的高血压。从机制上讲，基础和乙酰胆碱诱导的内皮细胞NO释放SKO apertas显着减少与野生型相比。SKO中内皮NO产生受损至少部分归因于EC中激动剂诱导的[Ca 2 +]（i）瞬变减少。因此，在野生型中沉默内皮S100 A1表达也减少了[Ca 2 +]（i）和NO的产生。此外，S100 A1在内皮细胞中的过表达进一步增加了NO的产生，这被肌醇-1，4，5-三磷酸受体阻断剂2-氨基乙氧基二苯基硼酸盐阻断。最后，心脏内皮细胞S100 A1的表达在体内心力衰竭中被下调。总的来说，内皮S100 A1关键地调节血管功能，因为S100 A1表达的缺乏导致[Ca 2 +]（i）和内皮NO释放减少，这至少部分地导致SKO小鼠中内皮依赖性血管舒张受损和高血压。因此，靶向内皮S100 A1表达可能是改善血管疾病或心力衰竭中内皮功能的新治疗手段。
S100A1, a Ca2+-binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca2+ handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca2+ ([Ca2+](i)) transients can be involved in important EC functions and endothelial NO synthase activity, we sought to investigate the impact of endothelial S100A1 on the regulation of endothelial and vascular function. Thoracic aortas from S100A1 knockout mice (SKO) showed significantly reduced relaxation in response to acetylcholine compared with wild-type vessels, whereas direct vessel relaxation using sodium nitroprusside was unaltered. Endothelial dysfunction attributable to the lack of S100A1 expression could also be demonstrated in vivo and translated into hypertension of SKO. Mechanistically, both basal and acetylcholine-induced endothelial NO release of SKO aortas was significantly reduced compared with wild type. Impaired endothelial NO production in SKO could be attributed, at least in part, to diminished agonist-induced [Ca2+](i) transients in ECs. Consistently, silencing endothelial S100A1 expression in wild type also reduced [Ca2+](i) and NO generation. Moreover, S100A1 overexpression in ECs further increased NO generation that was blocked by the inositol-1,4,5-triphosphate receptor blocker 2-aminoethoxydiphenylborate. Finally, cardiac endothelial S100A1 expression was shown to be downregulated in heart failure in vivo. Collectively, endothelial S100A1 critically modulates vascular function because lack of S100A1 expression leads to decreased [Ca2+](i) and endothelial NO release, which contributes, at least partially, to impaired endothelium-dependent vascular relaxation and hypertension in SKO mice. Targeting endothelial S100A1 expression may, therefore, be a novel therapeutic means to improve endothelial function in vascular disease or heart failure.