Endothelial dysfunction precedes atherosclerosis and is an independent predictor of cardiovascular events. Cholesterol levels and oxidative stress are key contributors to endothelial damage, whereas high levels of plasma high-density lipoproteins (HDL) could prevent it. Cholesteryl ester transfer protein (CETP) is one of the most potent endogenous negative regulators of HDL-cholesterol. However, whether and to what degree CETP expression impacts endothelial function, and the molecular mechanisms underlying the vascular effects of CETP on endothelial cells, have not been addressed. Acetylcholine-induced endothelium-dependent relaxation of aortic rings was impaired in human CETP-expressing transgenic mice, compared to their non-transgenic littermates. However, endothelial nitric oxide synthase (eNOS) activation was enhanced. The generation of superoxide and hydrogen peroxide was increased in aortas from CETP transgenic mice, while silencing CETP in cultured human aortic endothelial cells effectively decreased oxidative stress promoted by all major sources of ROS: mitochondria and NOX2. The endoplasmic reticulum stress markers, known as GADD153, PERK, and ARF6, and unfolded protein response effectors, were also diminished. Silencing CETP reduced endothelial tumor necrosis factor (TNF) α levels, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression, diminishing monocyte adhesion. These results support the notion that CETP expression negatively impacts endothelial cell function, revealing a new mechanism that might contribute to atherosclerosis.

中文翻译：

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内皮细胞中胆固醇酯转移蛋白（CETP）的存在会产生血管氧化应激和内皮功能障碍。

内皮功能障碍先于动脉粥样硬化，并且是心血管事件的独立预测因子。胆固醇水平和氧化应激是内皮损伤的关键因素，而血浆高密度脂蛋白（HDL）的高水平可预防胆固醇的破坏。胆固醇酯转移蛋白（CETP）是HDL-胆固醇中最有效的内源性负调节剂之一。然而，尚未讨论CETP表达是否以及在何种程度上影响内皮功能，以及CETP对内皮细胞的血管作用的潜在分子机制。与表达人类CETP的非转基因同窝仔相比，乙酰胆碱诱导的依赖于内皮的主动脉环松弛受到损害。但是，内皮一氧化氮合酶（eNOS）的激活得到增强。CETP转基因小鼠的主动脉中超氧化物和过氧化氢的生成增加，而在培养的人主动脉内皮细胞中沉默CETP则有效降低了由所有主要ROS线粒体和NOX2促进的氧化应激。内质网应激标记，称为GADD153，PERK和ARF6，以及未折叠的蛋白质反应效应子，也被减少。沉默CETP可降低内皮细胞肿瘤坏死因子（TNF）α水平，细胞间粘附分子1（ICAM-1）和血管粘附分子1（VCAM-1）的表达，从而减少单核细胞粘附。这些结果支持了CETP表达会对内皮细胞功能产生负面影响的观点，揭示了可能有助于动脉粥样硬化的新机制。