title: Reduction of no-reflow and reperfusion injury with the synthetic 17β-aminoestrogen compound Prolame is associated with PI3K/Akt/eNOS signaling cascade.
abstract: A high proportion of primary percutaneous coronary interventions performed in the setting of acute myocardial infarction, concur with inadequate myocardial perfusion at the microvascular level. This phenomenon, known as "no-reflow" contributes to reperfusion injury, poor prognosis and to unfavorable clinical outcome. In this study, we evaluated the hypothesis that the synthetic 17β-aminoestrogen Prolame, may confer cardioprotection and prevent against no-reflow. In an open-chest model of 30-min ischemia and 90-min reperfusion, male Wistar rats were randomly assigned to different groups: Control, Prolame, Prolame followed by the nitric oxide synthase inhibitor (L-NAME), and 17β-estradiol. Areas of risk, infarct size and no-reflow were determined by planimetry with triphenyltetrazolium chloride and thioflavin-S stains. Structural damage of the vasculature was measured as capillary compression in clarified tissue after intra-atrial injection of Microfil. Hemodynamic function was obtained at the end of stabilization, ischemia and reperfusion; nitric oxide (NO·) content was determined indirectly using the Griess reaction. Activation of the eNOS signaling cascade was determined by western blot. Prolame reduced the infarcted area, decreased the zones of no-reflow and capillary compression by activating the PI3K/Akt/eNOS signaling pathway in correlation with NO· increase. Prolame also activated endothelial cells augmenting NO· production, which was inhibited by ICI182780 (a selective estrogen receptor down-regulator), supporting the notion that the cardioprotective effect of Prolame involves the preservation of endothelium through the activation of estrogen receptor downstream signaling. Our results provide evidence that Prolame has potential therapeutic application in patients with AMI, as it prevents from both vascular and cardiac tissue damage.
authors.affiliation: Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, I. Ch., Juan Badiano No. 1. Colonia Sección XVI, Mexico, DF, 14080, Mexico.
authors.forename: Sauri
authors.initials: S
authors.lastname: Hernández-Reséndiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Palma-Flores
authors.forename: Sergio
authors.initials: S
authors.lastname: De Los Santos
authors.forename: Nadia G
authors.initials: NG
authors.lastname: Román-Anguiano
authors.forename: Mirthala
authors.initials: M
authors.lastname: Flores
authors.forename: Aurora
authors.initials: A
authors.lastname: de la Peña
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Flores
authors.forename: Juan M
authors.initials: JM
authors.lastname: Fernández-G
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Coral-Vázquez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Zazueta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D054318:No-Reflow Phenomenon / Q000378:metabolism / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014471:Umbilical Veins
chemical_list: D004963:Estrenes; C047867:prolame; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt