The presence of cholesteryl ester transfer protein (CETP) in endothelial cells generates vascular oxidative stress and endothelial dysfunction

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

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Article number69
Pages (from-to)1-16
Number of pages16
JournalBiomolecules
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2021
Externally publishedYes

Keywords

  • CETP
  • Endoplasmic reticulum stress
  • Endothelial dysfunction
  • Hydrogen peroxide
  • Icam-1
  • Mitochondria
  • Monocytes
  • Oxidative stress
  • Superoxide
  • Vcam-1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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