Treatment with an estrogen receptor-beta-selective agonist is cardioprotective

This study was designed to investigate whether treatment with an estrogen receptor-beta (ER-beta)-selective agonist (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN) can provide cardioprotection in female mice lacking endogenous estrogen. To study the effect of ER-beta stimulation in ischemia-reperfusion injury, we treated ovariectomized (ovx) female mice with 0.1 mg/kg/day of 17beta-estradiol, 0.8 mg/kg/day of DPN, or vehicle for 2 weeks. Isolated hearts were Langendorff perfused for 25 min prior to a 1-min treatment with isoproterenol, followed by 20 min of normothermic global ischemia and 40 min of reperfusion. Left ventricular developed pressure (LVDP) and heart rate were measured. Recovery of function at the end of 40 min of reperfusion was expressed as a percentage of pre-ischemic rate pressure product (RPP=LVDP x heart rate). Hearts from ovx female mice had a significantly lower recovery of LVDP than the hearts from intact female mice (12.4+/-1.6% vs. 19.6+/-1.6%, p<0.05, respectively). Furthermore, hearts from ovx female mice treated with DPN exhibited significantly better functional recovery than hearts from either vehicle-treated ovx female mice (20.1+/-2.2% vs. 12.4+/-1.6%, p<0.05, respectively) or wild type male mice (20.1+/-2.2% vs. 6.4+/-0.6%, p<0.05, respectively). DPN did not increase uterine weight in ovx females compared to vehicle treatment. Gene profiling showed that treatment with DPN resulted in upregulation of a number of protective genes such as heat shock protein 70, the antiapoptotic protein, growth arrest and DNA damage 45 beta, and cyclooxygenase 2.