CETP expression ameliorates endothelial function in female mice through estrogen receptor-α and endothelial nitric oxide synthase pathway

Author(s)

Lazaro, Carolina M. ; Victorio, Jamaira A. ; Davel, Ana Paula ; Oliveira, Helena C. F.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 325, n. 3, p. 9-pg., 2023-09-04.

Abstract

Endothelial dysfunction is an early manifestation of atherosclerosis. The cholesteryl ester transfer protein (CETP) has been considered proatherogenic by reducing plasma HDL levels. However, CETP may exhibit cell- or tissue-specific effects. We have previously reported that male mice expressing the human CETP gene show impaired endothelium-mediated vascular relaxation associated with oxidative stress. Although sexual dimorphisms on the metabolic role of CETP have been proposed, possible sex differences in the vascular effects of CETP were not previously studied. Thus, here we investigated the endothelial function of female CETP transgenic mice as compared with nontransgenic controls (NTg). Aortas from CETP females presented preserved endothelium-dependent relaxation to acetylcholine and an endothelium-dependent reduction of phenylephrine-induced contraction. eNOS phosphorylation (Ser1177) and calcium-induced NO levels were enhanced, whereas reactive oxygen species (ROS) production and NOX2 and SOD2 expression were reduced in the CETP female aortas. Furthermore, CETP females exhibited increased aortic relaxation to 17 beta-estradiol (E-2) and upregulation of heat shock protein 90 (HSP90) and caveolin-1, proteins that stabilize estrogen receptor (ER) in the caveolae. Indeed, CETP females showed an increased E-2-induced relaxation in a manner sensitive to estrogen receptor-alpha (ER alpha) and HSP90 inhibitors methylpiperidinopyrazole (MPP) and geldanamycin, respectively. MPP also impaired the relaxation response to acetylcholine in CETP but not in NTg females. Altogether, the study indicates that CETP expression ameliorates the anticontractile endothelial effect and relaxation to E-2 in females. This was associated with less ROS production, and increased eNOS-NO and E-2-ER alpha pathways. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk. (AU)

• 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: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/16505-8 - Perivascular adipose tissue dysfunction and inflammation in obesity: the role of mineralocorticoid receptors
• Grantee: Ana Paula Couto Davel
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/00543-8 - The role of endothelial and macrophage mineralocorticoid receptor in inflammation response and anti-contractile function of perivascular adipose tissue in obese male and female
• Grantee: Jamaira Aparecida Victorio
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/13862-7 - CETP influence on endothelial function and myocardial infarction: possible relation with mitochondrial function
• Grantee: Carolina Martins Lazaro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)