Cholesterol Enrichment Impairs Capacitative Calcium Entry, eNOS Phosphorylation & Shear Stress-Induced NO Production

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• 作者：Allison M. Andrews ; Tenderano T. Muzorewa…
• 关键词：Endothelial cells ; Nitric oxide ; Shear stress ; Atherosclerosis ; Cholesterol ; Capacitative calcium entry
• 刊名：Cellular and Molecular Bioengineering
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：10
• 期：1
• 页码：30-40
• 全文大小：
• 刊物类别：Engineering
• 刊物主题：Biomedical Engineering; Classical Mechanics; Continuum Mechanics and Mechanics of Materials; Biological and Medical Physics, Biophysics; Biomaterials; Cell Biology;
• 出版者：Springer US
• ISSN：1865-5033
• 卷排序：10

文摘

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.