| Autor: |
Wanschel ACBA; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil.; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA., Guizoni DM; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil., Lorza-Gil E; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil., Salerno AG; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil.; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA., Paiva AA; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil., Dorighello GG; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil., Davel AP; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil., Balkan W; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA.; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33146, USA., Hare JM; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA.; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33146, USA., Oliveira HCF; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, Brazil. |
| Abstrakt: |
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. |
