Abstract
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.
Highlights
Endothelial dysfunction (ED), which is a central feature of many cardiovascular diseases (CVDs), represents a powerful target in the development of new treatments
On aortic rings pre-contracted with 10−5 M phenylephrine, the maximal effect (Emax) and the half maximal effective concentration of acetylcholine-induced relaxation were both impaired in Cholesteryl ester transfer protein (CETP) Tg compared to non-transgenic mice (Ntg) mice
Aortas from CETP Tg mice showed decreased responsiveness and sensitivity to both sodium nitroprusside (SNP) and acetylcholine, as demonstrated by the significant rightward shift of the concentration-response curves compared with aortas from Ntg mice
Summary
Endothelial dysfunction (ED), which is a central feature of many cardiovascular diseases (CVDs), represents a powerful target in the development of new treatments. ED is directly associated with levels of LDL-cholesterol and inversely correlated with HDL-cholesterol. LDL-cholesterol through the use of statins has produced a remarkable >20% decrease in CVD events. Treatment with PCSK9 inhibitors reduces LDL-cholesterol by approximately. 45–60%, whether used alone or in combination with a statin [1]. The risk of a major cardiovascular event in patients with established coronary artery disease remains significant [2,3,4]. The risk of a major cardiovascular event in patients with established coronary artery disease remains significant [2,3,4]. 4.0/).
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