Abstract 1902: Role of SUR2 in Difference Genders of SUR2 Knockout Mutant Mice During Ischemic Preconditioning
Gender difference in ischemic protection exists with relatively lower myocardial infarction incidences in pre-menopausal females than age-matched males. Emerging evidence indicates that the female-specific advantage in protection is mediated by estrogen. Cardiac KATP channels (KATP) are known to comprise of a Kir6.2 pore and an SUR2 regulatory subunit. These channels are postulated to play essential roles in ischemic preconditioning (IPC) signaling and protection. In this study, we evaluated the ischemic responses in different genders of SUR2 knockout mutant mice, in which a 150-kDa SUR2 long variant (SUR2–150) was disrupted. An experimental ischemia model using intact mice was applied to compare the ischemic “phenotypes” in two genders. The mutant male mice (23%) were unexpectedly protected from ischemia with significantly smaller infarcts (n=5, P<0.05) than their WT controls (38%) as we previously reported. However, the mutant female mice showed significantly increased infarcts than WT female control mice. In WT female mice (n=4), the viable tissue ratio (red area over total area) was 37±5.5% while SUR2 mutant mice (n=4) had a markedly reduced ratio of 17±4.6% (p<0.05) suggesting that the mutant female mice were more susceptible to ischemic stress. Expression of SUR2–150 in WT male mice showed that its level decreased dramatically after IPC compared to non-preconditioned controls while the level of SUR2–150 increased in WT female mice after IPC compared to their controls. However, SUR2–150 was absent in mutants of both genders. Therefore, the down-regulation of SUR2–150 served as the “stimulus” in preconditioning signaling for WT male mice. The male mutant mice that had no SUR2–150 did not require the preconditioning procedure to reach a protective state. Moreover, expression levels of estrogen receptors, ERα and ERβ, were found to be upregulated in WT female mice after IPC but this upregulation was abolished in SUR2 female mutant mice. These results suggested that SUR2 is a target for estrogen receptors and losing SUR2–150 in female mice diminishes the estrogen effect. Our mouse models have provided new platforms to investigate molecular mechanisms and pathways underlying the gender-based difference in cardioprotection.
This research has received full or partial funding support from the American Heart Association, AHA National Center.