The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction

Author(s)

Wanschel, Amarylis C. B. A. ^{[1, 2]} ; Guizoni, Daniele M. ^[1] ; Lorza-Gil, Estela ^[1] ; Salerno, Alessandro G. ^{[1, 2]} ; Paiva, Adriene A. ^[1] ; Dorighello, Gabriel G. ^[1] ; Davel, Ana Paula ^[1] ; Balkan, Wayne ^{[2, 3]} ; Hare, Joshua M. ^{[2, 3]} ; Oliveira, Helena C. F. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, BR-13083970 Campinas - Brazil

^[2] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33146 - USA

^[3] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33146 - USA

• Document type: Journal article
• Source: BIOMOLECULES; v. 11, n. 1 JAN 2021.
• Web of Science Citations: 0

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) alpha 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. (AU)

• FAPESP's process: 16/01746-4 - Effects of mesenchymal stem cells (MSCs) on endothelial function: in vitro and in vivo studies.
• Grantee: Amarylis Claudine Bonito Azeredo Wanschel
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/05497-0 - Contribution of increased steroidogenesis and/or NADP-transhydrogenase deficiency to the mitochondrial oxidative stress in cells from hypercholesterolemic mice
• Grantee: Alessandro Gonzalez Salerno
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/09347-3 - Effect of the expression of the cholesteril ester transfer protein (CETP) on the endothelial function: studies in transgenic mice and in vitro
• Grantee: Amarylis Claudine Bonito Azeredo Wanschel
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/01044-0 - Effects of mesenchymal stem cell transplantation on oxidative stress in GSNOR-/- and C57BL6/J control mice.
• Grantee: Alessandro Gonzalez Salerno
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor