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.
Dept. of Pharmacology, Univ. of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
Erin A
EA
Booth
Nabeel R
NR
Obeid
Benedict R
BR
Lucchesi
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