The cardioprotective effects of estrogen receptor activation.

Recent experimental evidence suggests that biologically active 17beta-estradiol (E2) reduces the extent of irreversible myocardial injury following ischemia-reperfusion. However, the exact mechanism of this protection is unknown. Work described in this dissertation evaluated the effects of E2 and estrogen receptor selective compounds on infarct size after ischemia-reperfusion. The first two studies of this dissertation evaluated the effects of estrogen on infarct size and determined if the protective effects of estrogen were altered when progestin was added to the treatment regimen. Estrogen administered thirty minutes before ischemia protected the myocardium, was dependent on the estrogen receptor (ER), and the reduction in infarct size was reversed by the addition of the progestin medroxyprogesterone acetate. The third study used compounds selective for specific subtypes of the ER to determine which subtype is required for the protective effects of E2. Myocardial salvage was achieved with acute administration of the ERalpha selective agonist 4,4,4-(4-propyl-(1H)-pyrazole-1,3,5-triyl)tris-phenol. No protection was observed following administration of the ERbeta selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile. These studies indicate that activation of ERalpha is required for myocardial protection after acute E2 administration. The fourth study combined the cyclooxygenase-2 (COX-2) inhibitor nimesulide and E2 to test the hypothesis that the protection conferred by E2 requires COX-2 activation. Pretreatment with nimesulide inhibited the protective effects of acute E2 administration indicating that COX-2 plays a role in E2-mediated myocardial protection. The second part of this study as well as the final study of this thesis evaluated the effects of two ER-selective compounds on infarct reduction after ischemia-reperfusion. Acute administration of the selective estrogen receptor modulator tamoxifen and the pathway selective ER ligand WAY-169916 were evaluated in the in vivo model of ischemia-reperfusion. Both tamoxifen and WAY-169916 significantly reduced infarct size when expressed as a percent of area at risk. Together these studies show that E2 protects the myocardium from ischemia and reperfusion via activation of ERalpha and, in part, subsequent activation of COX-2. E2 was also shown to inhibit the inflammatory response after ischemia and reperfusion. The effects of estrogens on the cardiovascular system remain complex and a number of questions must still be addressed. The goal of future research is to further understand the mechanism of the protective effects of estrogen in order to develop therapeutics that enhance estrogen s cardioprotective effects in postmenopausal women while limiting the unwanted side effects.Ph.D.Health and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125618/2/3208426.pd