Cholesterol Enrichment Impairs Capacitative Calcium Entry, eNOS Phosphorylation & Shear Stress-Induced NO Production.
Cholesterol Enrichment Impairs Capacitative Calcium Entry, eNOS Phosphorylation & Shear Stress-Induced NO Production.
复制标题
胆固醇富集会损害电容性钙进入，eNOS磷酸化和剪切应力引起的无产生。
DOI：
10.1007/s12195-016-0456-5
复制
发表时间：
2017-02
影响因子：
2.8
通讯作者：
Barbee KA
中科院分区：
文献类型：
--
作者：
Andrews AM;Muzorewa TT;Zaccheo KA;Buerk DG;Jaron D;Barbee KA
内皮功能障碍，其特征在于一氧化氮（NO）的产生或可用性降低，被广泛认为是早期动脉粥样硬化的标志。此外，高胆固醇血症被认为是动脉粥样硬化发展的主要风险因素，并与血流诱导的扩张受损相关。然而，胆固醇水平升高导致NO产生减少的机制尚不清楚。NO的释放响应于剪切应力和激动剂诱发的细胞内钙的变化。尽管钙信号传导很复杂，但我们之前已经证明，内皮型一氧化氮合酶（eNOS）的NO产生优先被通过钙库操纵通道的钙内流激活。我们假设，胆固醇富集改变了这一信号通路（称为电容性钙进入; CCE），最终导致NO减少。我们的研究结果表明，胆固醇富集废除ATP诱导的eNOS磷酸化和衰减的钙反应的优先抑制CCE。此外，胆固醇富集还抑制剪切应力诱导的NO产生和eNOS磷酸化，与我们先前的结果一致，表明ATP自分泌刺激和随后的CCE激活在内皮流动反应中的重要作用。
Endothelial dysfunction, characterized by decreased production or availability of nitric oxide (NO), is widely believed to be the hallmark of early-stage atherosclerosis. In addition, hypercholesterolemia is considered a major risk factor for development of atherosclerosis and is associated with impaired flow-induced dilation. However, the mechanism by which elevated cholesterol levels leads to decreased production of NO is unclear. NO is released in response to shear stress and agonist-evoked changes in intracellular calcium. Although calcium signaling is complex, we have previously shown that NO production by endothelial nitric oxide synthase (eNOS) is preferentially activated by calcium influx via store-operated channels. We hypothesized that cholesterol enrichment altered this signaling pathway (known as capacitive calcium entry; CCE) ultimately leading to decreased NO. Our results show that cholesterol enrichment abolished ATP-induced eNOS phosphorylation and attenuated the calcium response by the preferential inhibition of CCE. Furthermore, cholesterol enrichment also inhibited shear stress-induced NO production and eNOS phosporylation, consistent with our previous results showing a significant role for ATP autocrine stimulation and subsequent activation of CCE in the endothelial flow response.