Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury

Under hypercontractile conditions associated with increased intracellular calcium, male hearts show enhanced ischemia/reperfusion injury compared to female hearts. Our aim in this study was to identify the specific estrogen receptor involved in this gender difference. Following brief treatment with isoproterenol, isolated mouse hearts were subjected to ischemia and reperfusion. Postischemic contractile function and infarct size were measured in wild-type (WT) male and female hearts, and female hearts lacking functional alpha estrogen receptor (αERKO), or the beta estrogen receptor (βERKO). WT male hearts exhibited significantly less functional recovery and more necrosis than WT females. αERKO female hearts exhibited ischemia/reperfusion injury similar to that observed in WT females, whereas βERKO females exhibited significantly less functional recovery than WT females and were similar to WT males. These data suggest that estrogen, through the β-estrogen receptor, plays a role in the protection observed in the female heart. Furthermore, we identified genes that were differentially expressed in βERKO female hearts compared to αERKO and WT female hearts, and found altered expression of a number of metabolism genes, which may be important in ischemic injury. We further showed that WT female hearts have increased ratio of carbohydrate to fatty acid metabolism relative to WT males.