TY - JOUR
T1 - The presence of cholesteryl ester transfer protein (CETP) in endothelial cells generates vascular oxidative stress and endothelial dysfunction
AU - Wanschel, Amarylis C.B.A.
AU - Guizoni, Daniele M.
AU - Lorza-Gil, Estela
AU - Salerno, Alessandro G.
AU - Paiva, Adriene A.
AU - Dorighello, Gabriel G.
AU - Davel, Ana Paula
AU - Balkan, Wayne
AU - Hare, Joshua M.
AU - Oliveira, Helena C.F.
N1 - Funding Information:
This work was supported by grants from the Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo to H.C.F.O. (FAPESP # 2011/50400-0 and 2013/07607-8) and Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq # 310546/2014-1). A.C.B.A.W. and A.G.S. were supported by FAPESP (#13/09347-3, #16/01746-4; #13/05497-0, #16/01044-0) E.L.-G. and A.A.P. were supported by CAPES (Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior). D.M.G. and G.G.D. were supported by CNPq.
Funding Information:
Funding: This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo to H.C.F.O. (FAPESP # 2011/50400-0 and 2013/07607-8) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq # 310546/2014-1). A.C.B.A.W. and A.G.S. were supported by FAPESP (#13/09347-3, #16/01746-4; #13/05497-0, #16/01044-0) E.L.-G. and A.A.P. were supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). D.M.G. and G.G.D. were supported by CNPq.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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 HDLcholesterol. 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.
AB - 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 HDLcholesterol. 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.
KW - CETP
KW - Endoplasmic reticulum stress
KW - Endothelial dysfunction
KW - Hydrogen peroxide
KW - Icam-1
KW - Mitochondria
KW - Monocytes
KW - Oxidative stress
KW - Superoxide
KW - Vcam-1
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U2 - 10.3390/biom11010069
DO - 10.3390/biom11010069
M3 - Article
C2 - 33430172
AN - SCOPUS:85099093998
VL - 11
SP - 1
EP - 16
JO - Biomolecules
JF - Biomolecules
SN - 2218-273X
IS - 1
M1 - 69
ER -