title: Intraluminal-restricted 17 beta-estradiol exerts the same myocardial protection against ischemia/reperfusion injury in vivo as free 17 beta-estradiol.
abstract: 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.
authors.affiliation: Seccion de Graduados, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico.
authors.forename: Arturo
authors.initials: A
authors.lastname: Rodriguez-Hernandez
authors.forename: Ivan
authors.initials: I
authors.lastname: Rubio-Gayosso
authors.forename: Israel
authors.initials: I
authors.lastname: Ramirez
authors.forename: Israel
authors.initials: I
authors.lastname: Ita-Islas
authors.forename: Eduardo
authors.initials: E
authors.lastname: Meaney
authors.forename: Samuel
authors.initials: S
authors.lastname: Gaxiola
authors.forename: Alejandra
authors.initials: A
authors.lastname: Meaney
authors.forename: Juan
authors.initials: J
authors.lastname: Asbun
authors.forename: Lauro
authors.initials: L
authors.lastname: Figueroa-Valverde
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
mesh_terms: D000818:Animals; D003911:Dextrans / Q000627:therapeutic use*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D004967:Estrogens / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003911:Dextrans; D004967:Estrogens; D004958:Estradiol; D051058:Oncogene Protein v-akt; D051571:Protein Kinase C-alpha