Effect of the expression of the cholesteril ester transfer protein (CETP) on the endothelial function: studies in transgenic mice and in vitro

• Grant number: 13/09347-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2013
• End date: May 31, 2017
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Coutinho Franco de Oliveira
• Grantee: Amarylis Claudine Bonito Azeredo Wanschel
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 16/01746-4 - Effects of mesenchymal stem cells (MSCs) on endothelial function: in vitro and in vivo studies., BE.EP.PD

Abstract

Cholesteryl transfer protein (CETP) is a protein that promotes plasma lipoprotein remodeling and modulates atherosclerotic risk. We have recently proposed that it has anti-oxidative, anti-inflammatory and anti-adipogenic functions. In this proposal, we have hypothesized that CETP has an additional role in promoting alterations in nitric oxide bioavailability and consequently in the endothelial function and atherogenesis. CETP could have a beneficial action on the endothelial function if one considers that CETP reduces plasma free cholesterol levels and probably the cholesterol content of endothelial cell membrane. The reduction of cell membrane cholesterol decreases the eNOS-Cav1 interaction and stability in the caveola, increasing NO production. Alternatively, considering that CETP reduces HDL plasma levels and that HDL decreases eNOS-Cav-1 interactions, CETP would impair endothelial function. There are evidences in favor of the first possibility in hypertensive rats treated with the CETP inhibitor, torcetrabip, which resulted in endothelial function impairment. Therefore, our study aims at investigating the effect of CETP expression on endothelial function and vascular reactivity. Once we establish the effect, we will investigate the possible mechanisms modulated by CETP (membrane cholesterol content, eNOS localization and activity, NO bioavailability, redox and/or inflammation modifications, signaling pathways involved). For this purpose, we will carry out in vivo studies in transgenic (Tg) mice expressing human CETP as compared to non-transgenic littermates (nTg) that do not express this protein. The animals will be studied in their basal state and after high fat diet feeding. This treatment induces inflammation and oxidative stress in the vessel walls of these animals. We propose that CETP has anti-oxidative and anti-inflammatory functions, and thus, CETP Tg mice can respond better to these treatments. Additionally, we will investigate human endothelial cell lines with CETP expression repressed by RNAi.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

WANSCHEL, AMARYLIS C. B. A.; GUIZONI, DANIELE M.; LORZA-GIL, ESTELA; SALERNO, ALESSANDRO G.; PAIVA, ADRIENE A.; DORIGHELLO, GABRIEL G.; DAVEL, ANA PAULA; BALKAN, WAYNE; HARE, JOSHUA M.; OLIVEIRA, HELENA C. F.. The Presence of Cholesteryl Ester Transfer Protein (CETP) in Endothelial Cells Generates Vascular Oxidative Stress and Endothelial Dysfunction. BIOMOLECULES, v. 11, n. 1, JAN 2021. (16/01746-4, 13/05497-0, 11/50400-0, 13/07607-8, 13/09347-3, 16/01044-0)