Departments of Obstetrics & Gynecology, University of Alberta, Edmonton, Canada.
J Leukoc Biol. 2012 Jun;91(6):947-56. doi: 10.1189/jlb.1011513. Epub 2012 Mar 27.
NO, produced by the endothelium, is a modulator of vascular inflammation. Traditionally, eNOS was believed to be the primary source of NO in the endothelium. However, recent data suggest an important role for nNOS in the endothelium, although little is known about factors regulating this novel eNOS. We examined the localization, regulation, and significance of endothelial nNOS in this study. Primary HUVECs were used as a model system. Inflammatory changes were induced by stimulation with TNF. We report that unlike eNOS, nNOS is predominantly localized to the nucleus of resting endothelial cells. This nNOS also contributed to basal NO production in the resting endothelium. Ablation of endothelial nNOS by pharmacological inhibition (using L-NPA) or siRNA further enhanced cytokine-mediated inflammatory responses, such as up-regulation of VCAM-1 and proinflammatory cytokines, as well as increased leukocyte recruitment. Based on these findings, we suggest a potential anti-inflammatory role of endothelial nNOS that can attenuate unopposed, proinflammatory cytokine actions. Our data indicate a novel location and an immunoregulatory role for nNOS in the endothelium.
内皮细胞产生的一氧化氮合酶（NO）是血管炎症的调节剂。传统上，内皮型一氧化氮合酶（eNOS）被认为是内皮细胞中 NO 的主要来源。然而，最近的数据表明，神经元型一氧化氮合酶（nNOS）在血管内皮中也起着重要作用，尽管人们对调节这种新型 eNOS 的因素知之甚少。在这项研究中，我们研究了内皮细胞 nNOS 的定位、调节及其意义。我们使用原代脐静脉内皮细胞（HUVECs）作为模型系统。通过用 TNF 刺激诱导炎症变化。我们报告说，与 eNOS 不同，nNOS 主要定位于静止内皮细胞的核内。这种 nNOS 也有助于静止内皮细胞中基础 NO 的产生。通过药理学抑制（使用 L-NPA）或 siRNA 去除内皮 nNOS，进一步增强了细胞因子介导的炎症反应，如 VCAM-1 和促炎细胞因子的上调，以及白细胞募集的增加。基于这些发现，我们提出内皮细胞 nNOS 具有潜在的抗炎作用，可以减弱不受抑制的促炎细胞因子的作用。我们的数据表明 nNOS 在血管内皮中具有新的定位和免疫调节作用。
