Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, Brazil.
Am J Physiol Heart Circ Physiol. 2023 Sep 1;325(3):H592-H600. doi: 10.1152/ajpheart.00365.2023. Epub 2023 Aug 4.
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 17β-estradiol (E) 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-induced relaxation in a manner sensitive to estrogen receptor-α (ERα) 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 in females. This was associated with less ROS production, and increased eNOS-NO and E-ERα pathways. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk. Here we demonstrated that CETP expression has a sex-specific impact on the endothelium function. Contrary to what was described for males, CETP-expressing females present preserved endothelium-dependent relaxation to acetylcholine and improved relaxation response to 17β-estradiol. This was associated with less ROS production, increased eNOS-derived NO, and increased expression of proteins that stabilize estrogen receptor-α (ERα), thus increasing E-ERα signaling sensitivity. These results highlight the need for considering the sex-specific effects of CETP on cardiovascular risk.
内皮功能障碍是动脉粥样硬化的早期表现。胆固醇酯转移蛋白（CETP）通过降低血浆高密度脂蛋白（HDL）水平被认为具有致动脉粥样硬化作用。然而，CETP 可能表现出细胞或组织特异性效应。我们之前曾报道过，表达人 CETP 基因的雄性小鼠表现出与氧化应激相关的受损内皮介导的血管舒张。尽管已经提出了 CETP 在代谢作用上的性别二态性，但 CETP 对血管的可能性别差异尚未得到研究。因此，在这里，我们研究了雌性 CETP 转基因小鼠与非转基因对照（NTg）相比的内皮功能。CETP 雌性的主动脉对乙酰胆碱的内皮依赖性舒张保持不变，并且对苯肾上腺素诱导的收缩的内皮依赖性减少。eNOS 磷酸化（Ser1177）和钙诱导的 NO 水平增强，而活性氧（ROS）产生以及 NOX2 和 SOD2 的表达在 CETP 雌性主动脉中降低。此外，CETP 雌性对 17β-雌二醇（E）的主动脉松弛增加，并上调热休克蛋白 90（HSP90）和 caveolin-1，这些蛋白可将雌激素受体（ER）稳定在 caveolae 中。实际上，CETP 雌性以对雌激素受体-α（ERα）和热休克蛋白 90 抑制剂甲哌啶吡唑（MPP）和格尔德霉素分别敏感的方式显示出增强的 E 诱导的松弛。MPP 还损害了 CETP 但不损害 NTg 雌性的乙酰胆碱松弛反应。总而言之，该研究表明 CETP 表达改善了雌性的抗收缩性内皮作用和对 E 的松弛反应。这与 ROS 产生减少以及 eNOS-NO 和 E-ERα 途径增加有关。这些结果突出表明需要考虑 CETP 对心血管风险的性别特异性影响。在这里，我们证明了 CETP 表达对女性的内皮功能具有性别特异性影响。与对雄性所描述的相反，表达 CETP 的雌性对乙酰胆碱的内皮依赖性舒张保持不变，并且对 17β-雌二醇的松弛反应增强。这与 ROS 产生减少，eNOS 衍生的 NO 增加以及稳定雌激素受体-α（ERα）的蛋白表达增加有关，从而增加了 E-ERα 信号敏感性。这些结果突出表明需要考虑 CETP 对心血管风险的性别特异性影响。
