Rodriguez-Hernandez Arturo, Rubio-Gayosso Ivan, Ramirez Israel, Ita-Islas Israel, Meaney Eduardo, Gaxiola Samuel, Meaney Alejandra, Asbun Juan, Figueroa-Valverde Lauro, Ceballos Guillermo
Seccion de Graduados, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico.
Steroids. 2008 May;73(5):528-38. doi: 10.1016/j.steroids.2008.01.003. Epub 2008 Jan 17.
Several in vitro studies show that in animals and isolated cells, 17 beta-estradiol induces cardiovascular protective effects and it has also been observed that it reduces coronary heart disease risk. However, the use of estrogens to improve or protect cardiovascular function in humans has been controversial, this might be explained by the wide variety of effects, because estrogen receptors (ER) are expressed ubiquitously. Therefore, a cell-specific targeting therapeutic approach might be necessary. 17 beta-Estradiol was coupled to a large modified dextran through an aminocaproic spacer. For this study we used intact and gonadectomized male Wistar rats, 15 days after surgical procedure. Intravascular administration of 17 beta-estradiol-macromolecular conjugate, prior to coronary reperfusion diminishes the area of damage induced by coronary ischemia reperfusion (I/R) injury on an in vivo model. This effect was observed at 17 beta-estradiol sub-physiological concentrations [0.01 nmol/L], it is mediated by luminal endothelial ER alpha activation. 17 beta-Estradiol-macromolecular conjugate decreases phosphorylation level of PKC alpha and Akt, as part of the process to induce myocardial protection against coronary I/R. We proved that the hormone-macromolecular conjugate labeled with [3H]estradiol remained confined in the intravascular space the conjugate was not internalized into organs like heart, lung or liver. It is noteworthy that the 17 beta-estradiol-macromolecular conjugate has a slow renal elimination, which might increase its pharmacological advantage. We concluded that the stimulus of endothelial estrogen receptors is enough to decrease the myocardial damage induced by coronary reperfusion.
多项体外研究表明，在动物和分离细胞中，17β-雌二醇具有心血管保护作用，并且也观察到它能降低冠心病风险。然而，在人类中使用雌激素来改善或保护心血管功能一直存在争议，这可能是由于其作用的多样性所致，因为雌激素受体（ER）广泛表达。因此，可能需要一种细胞特异性靶向治疗方法。17β-雌二醇通过一个氨基己酸间隔物与一个大的修饰葡聚糖偶联。在本研究中，我们使用了完整的和去势的雄性Wistar大鼠，手术15天后进行实验。在冠状动脉再灌注前血管内给予17β-雌二醇-大分子偶联物，可减少体内模型中冠状动脉缺血再灌注（I/R）损伤所诱导的损伤面积。在17β-雌二醇亚生理浓度[0.01 nmol/L]时观察到这种效应，它是由腔内内皮ERα激活介导的。17β-雌二醇-大分子偶联物降低PKCα和Akt的磷酸化水平，作为诱导心肌抵抗冠状动脉I/R保护过程的一部分。我们证明，用[3H]雌二醇标记的激素-大分子偶联物仍局限于血管内空间，该偶联物未内化到心脏、肺或肝脏等器官中。值得注意的是，17β-雌二醇-大分子偶联物经肾脏清除缓慢，这可能会增加其药理学优势。我们得出结论，内皮雌激素受体的刺激足以减少冠状动脉再灌注所诱导的心肌损伤。
