Costa Tiago J, Ceravolo Graziela S, Echem Cinthya, Hashimoto Carolina M, Costa Beatriz P, Santos-Eichler Rosangela A, Oliveira Maria Aparecida, Jiménez-Altayó Francesc, Akamine Eliana H, Dantas Ana Paula, Carvalho Maria Helena C
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Front Physiol. 2018 May 8;9:490. doi: 10.3389/fphys.2018.00490. eCollection 2018.
Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the association of testosterone to conventional hormonal therapy. Testosterone has been linked to development of cardiovascular diseases including hypertension and it also increases cytochrome -450-induced 20-HETE synthesis which in turn results in vascular dysfunction. However, the effect of testosterone plus estrogen in the cardiovascular system is still very poorly studied. The aim of the present study is to evaluate the role of cytochrome -450 pathway in a postmenopausal hypertensive female treated with testosterone plus estrogen. For that, hypertensive ovariectomized rats (OVX-SHR) were used as a model of postmenopausal hypertension and four groups were created: SHAM-operated (SHAM), ovariectomized SHR (OVX), OVX treated for 15 days with conjugated equine estrogens [(CEE) 9.6 μg/Kg/day/po] or CEE associated to testosterone [(CEE+T) 2.85 mg/kg/weekly/im]. Phenylephrine-induced contraction and generation of reactive oxygen species (ROS) were markedly increased in aortic rings from OVX-SHR compared to SHAM rats which were restored by CEE treatment. On the other hand, CEE+T abolished vascular effects by CEE and augmented both systolic and diastolic blood pressure of SHR. Treatment of aortic rings with the CYP/20-HETE synthesis inhibitor HET0016 (1 μM) reduced phenylephrine hyperreactivity and the augmented ROS generation in the CEE+T group. These results are paralleled by the increased CYP4F3 protein expression and activity in aortas of CEE+T. In conclusion, we showed that association of testosterone to estrogen therapy produces detrimental effects in cardiovascular system of ovariectomized hypertensive females via CYP4F3/20-HETE pathway. Therefore, our findings support the standpoint that the CYP/20-HETE pathway is an important therapeutic target for the prevention of cardiovascular disease in menopausal women in the presence of high levels of testosterone.
绝经后期与潮热、外阴阴道萎缩、性欲减退障碍（HSDD）等不同症状相关。临床研究表明，患有HSDD的绝经后女性可从睾酮与传统激素疗法联合使用中获益。睾酮与包括高血压在内的心血管疾病的发生有关，并且它还会增加细胞色素P450诱导的20-羟基二十碳四烯酸（20-HETE）的合成，进而导致血管功能障碍。然而，睾酮加雌激素对心血管系统的影响仍研究甚少。本研究的目的是评估细胞色素P450途径在接受睾酮加雌激素治疗的绝经后高血压女性中的作用。为此，将高血压去卵巢大鼠（OVX-SHR）用作绝经后高血压模型，并分为四组：假手术组（SHAM）、去卵巢SHR组（OVX）、用结合马雌激素[（CEE）9.6μg/Kg/天/口服]治疗15天的OVX组或与睾酮联合使用的CEE组[（CEE+T）2.85mg/kg/周/肌肉注射]。与SHAM大鼠相比，OVX-SHR主动脉环中去氧肾上腺素诱导的收缩和活性氧（ROS）的产生明显增加，而CEE治疗可使其恢复。另一方面，CEE+T消除了CEE的血管效应，并升高了SHR的收缩压和舒张压。用CYP/20-HETE合成抑制剂HET0016（1μM）处理主动脉环可降低去氧肾上腺素的高反应性，并减少CEE+T组中ROS生成的增加。这些结果与CEE+T组主动脉中CYP4F3蛋白表达和活性的增加相一致。总之，我们表明，睾酮与雌激素疗法联合使用会通过CYP4F3/20-HETE途径对去卵巢高血压女性的心血管系统产生有害影响。因此，我们的研究结果支持这样的观点，即在存在高水平睾酮的情况下，CYP/20-HETE途径是预防绝经后女性心血管疾病的重要治疗靶点。
