The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction
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 pr...
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doaj-6e5b59f4fb194832873252fbe9e0250e2021-01-08T00:00:04ZengMDPI AGBiomolecules2218-273X2021-01-0111696910.3390/biom11010069The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial DysfunctionAmarylis C. B. A. Wanschel0Daniele M. Guizoni1Estela Lorza-Gil2Alessandro G. Salerno3Adriene A. Paiva4Gabriel G. Dorighello5Ana Paula Davel6Wayne Balkan7Joshua M. Hare8Helena C. F. Oliveira9Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilDepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilInterdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USAInterdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USADepartment of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-970, BrazilEndothelial 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.https://www.mdpi.com/2218-273X/11/1/69CETPoxidative stressendoplasmic reticulum stressendothelial dysfunctionsuperoxidehydrogen peroxide |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amarylis C. B. A. Wanschel Daniele M. Guizoni Estela Lorza-Gil Alessandro G. Salerno Adriene A. Paiva Gabriel G. Dorighello Ana Paula Davel Wayne Balkan Joshua M. Hare Helena C. F. Oliveira |
spellingShingle |
Amarylis C. B. A. Wanschel Daniele M. Guizoni Estela Lorza-Gil Alessandro G. Salerno Adriene A. Paiva Gabriel G. Dorighello Ana Paula Davel Wayne Balkan Joshua M. Hare Helena C. F. Oliveira The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction Biomolecules CETP oxidative stress endoplasmic reticulum stress endothelial dysfunction superoxide hydrogen peroxide |
author_facet |
Amarylis C. B. A. Wanschel Daniele M. Guizoni Estela Lorza-Gil Alessandro G. Salerno Adriene A. Paiva Gabriel G. Dorighello Ana Paula Davel Wayne Balkan Joshua M. Hare Helena C. F. Oliveira |
author_sort |
Amarylis C. B. A. Wanschel |
title |
The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction |
title_short |
The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction |
title_full |
The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction |
title_fullStr |
The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction |
title_full_unstemmed |
The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction |
title_sort |
presence of cholesteryl ester transfer protein (cetp) in endothelial cells generates vascular oxidative stress and endothelial dysfunction |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2021-01-01 |
description |
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. |
topic |
CETP oxidative stress endoplasmic reticulum stress endothelial dysfunction superoxide hydrogen peroxide |
url |
https://www.mdpi.com/2218-273X/11/1/69 |
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