Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue

Author(s)

Lazaro, C. M. ; Freitas, I. N. ; Nunes, V. S. ; Guizoni, D. M. ; Victorio, J. A. ; Oliveira, H. C. F. ; Davel, A. P.

• Document type: Journal article
• Source: FUNCTION; v. 5, n. 4, p. 13-pg., 2024-07-11.

Abstract

Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP. Graphical Abstract (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: 20/09799-5 - Microparticles and endothelial function in patients with COVID-19: effects of bradykinin blockade
• Grantee: Ana Paula Couto Davel
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/26080-4 - Characterization of molecular and functional mechanisms involved in endocrine-metabolic, cardiovascular and neural dysfunctions induced by the restriction of amino acids in vitro and in vivo: possible therapeutic role of bile acid TUDCA
• Grantee: Everardo Magalhães Carneiro
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/15164-5 - Molecular and functional mechanisms involved in the effects of TUDCA bile acid on perivascular adipose tissue in protein restriction
• Grantee: Israelle Netto Freitas
• Support Opportunities: Scholarships in Brazil - Doctorate
• 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)