Activation of estrogen receptor-alpha protects the in vivo rabbit heart from ischemia-reperfusion injury.
The estrogen receptor (ER) mediates estrogenic activity in a variety of organs, including those in the reproductive, cardiovascular, immune, and central nervous systems. Experimental studies have demonstrated that 17beta-estradiol (E2) protects the heart from ischemia-reperfusion injury. Two estrogen receptors, ER alpha and ER beta, mediate the actions of estrogen; however, it is not certain which ER mediates the cardioprotective effects of E2. In the present study, the ER-selective agonists 4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; ER alpha) and 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ER beta) were assessed for their cardioprotective potential in an in vivo rabbit model of ischemia-reperfusion injury. Anesthetized female rabbits were administered PPT (3 mg/kg), DPN (3 mg/kg), E2 (20 microg/rabbit), or vehicle intravenously 30 min before a 30-min occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Acute treatment with E2 (17.7 +/- 2.9%; P < 0.001) and PPT (18.1 +/- 2.9%; P < 0.001), but not DPN (45.3 +/- 2.4%) significantly decreased infarct size as a percent of area at risk compared with vehicle (45.3 +/- 2.4%). Coadministration of PPT or E2 with the ER antagonist ICI-182,780 limited the infarct size-sparing effect of the compounds (43.8 +/- 6.6% and 40.6 +/- 5.7% respectively, expressed as a percentage of risk region). PPT reduced the release of cardiac-specific troponin-I and reduced the tissue deposition of the membrane attack complex and C-reactive protein similar to that of E2. The results indicate that activation of ER alpha, but not ER beta, is required for the observed cardioprotective effects of E2.
Booth
Erin A
EA
Dept. of Pharmacology, Univ. of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
Obeid
Nabeel R
NR
Lucchesi
Benedict R
BR
D000818:Animals; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists; D005260:Female; D005455:Fluorescent Antibody Technique; D000077267:Fulvestrant; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000502:physiology; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy; D010636:Phenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D019210:Troponin I / Q000378:metabolism; D011422:Propionates
D015415:Biomarkers; D002097:C-Reactive Protein; D015938:Complement Membrane Attack Complex; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D000077267:Fulvestrant; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D019210:Troponin I; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol