Estrogen-induced SDF-1 production is mediated by estrogen receptor-α in female hearts after acute ischemia and reperfusion

Background. Gender differences exist in myocardial response to acute ischemia/reperfusion (I/R) injury and estrogen mediates cardioprotection in the female heart after I/R. Accumulating evidence has indicated that stromal cell-derived factor-1 (SDF-1) is increased in the ischemic heart and initiates cardioprotective effects. However, it is unknown whether SDF-1 plays a role in gender-specific response to myocardial I/R and in estrogen-induced acute protection. Therefore, we hypothesize that (1) increased SDF-1 production will be observed in female hearts compared with male hearts in response to I/R, which is attributable to the effect of estrogen; and that (2) estrogen receptor (ER)alpha, not ER beta mediates estrogen-contributed SDF-1 expression in female hearts after I/R. Methods. Heart tissue subjected to I/R injury was assessed for myocardial expression of SDF-1 (by enzyme-linked immunosorbent assay) and SDF-1 receptor-CXCR4 (Western blot). Groups were as follows: Rat hearts from adult male, female, ovariectomized female (OVX F), and male and OVX F supplemented with chronic 17 beta-estradiol (E2), and mouse hearts from adult male and female wild-type, ER alpha knockout (ER alpha KO) and ER beta KO. Results. I/R significantly increased myocardial SDF-1 expression in both genders. Higher levels of SDF-1 existed in female hearts after I/R compared with males. Depletion of endogenous estrogen by ovariectomy reduced cardiac SDF-1 production in females after I/R. E2 supplementation significantly restored SDF-1 expression in OVX F and males compared with their counterparts. Notably, ablation of ER alpha, not ER beta, markedly decreased SDF-1 production in females alter I/R. Unlike SDF-1, cardiac CXCR4 expression was not affected by gender, sex hormone, or ERs in the ischemic heart. Conclusion. Our study represents the first evidence that female hearts exhibit higher levels of SDF-1 expression compared with males after acute I/R. This increased myocardial SDF-1 production in females is partly owing to effect of estrogen through ER alpha, but not ER beta. (Surgery 2011;150:197-203.)