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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 325, n. 3, p. 9-pg., 2023-09-04.

Resumo

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)

• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/17728-8 - Função e disfunção mitocondrial: implicações para o envelhecimento e doenças associadas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/16505-8 - Disfunção e inflamação do tecido adiposo perivascular na obesidade: papel do receptor de mineralocorticoides
• Beneficiário: Ana Paula Couto Davel
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/00543-8 - Papel do receptor de mineralocorticoides endoteliais e de macrófagos na resposta inflamatória e função anticontrátil do tecido adiposo perivascular de machos e fêmeas obesos
• Beneficiário: Jamaira Aparecida Victorio
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/13862-7 - Influência da CETP na função endotelial e no infarto do miocárdio: possível relação com função mitocondrial
• Beneficiário: Carolina Martins Lazaro
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto