Estrogen-induced SDF-1 production is mediated by estrogen receptor-α in female hearts after acute ischemia and reperfusion
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Abstract
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)α, not ERβ 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 17β-estradiol (E2), and mouse hearts from adult male and female wild-type, ERα knockout (ERαKO) and ERβKO.
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 ERα, not ERβ, markedly decreased SDF-1 production in females after 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 ERα, but not ERβ.