Abstract 18164: The Effect of Sex Chromosomes on Myocardial Ischemia/Reperfusiong Injury

Abstract

Introduction: Sex differences in susceptibility to ischemia/reperfusion(I/R) injury have been demonstrated both in basic and clinical settings. Female hearts show better functional recovery after I/R injury compared with males. Most of these sex differences in I/R settings have been attributed to sex hormones. Here we used two unique mouse models (four core genotypes mice and XY* mice) to investigate the role of sex chromosomes on cardiac I/R injury. Methods: We used two unique mouse models of “four core genotypes” (FCG) (XX mice with ovaries or testes and XY mice with ovaries and testes) and XY* (mice with one X chromosome (XO or XY) or with two X chromosomes (XX or XXY). All mice were gonadectomized at day75 and used 30 days after gonadectomy to eliminate the effects of gonadal hormones. Isolated hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion to measure heart function and infarct size. There were 4-7 mice per group. Two way ANOVA was used for statistical analysis. P<0.05 was considered statistically significant. Values are expressed as mean± SE. Results: In both FCG and XY* models, the cardiac function was similar among all groups before ischemia. However postischemic function of XX mice was significantly lower than XY, irrespective of gonadal sex (recovery of rate pressure product (RPP): 31.2±5.7% in XX females and 44.7±8.8% in XX males vs. 56.6±5.8% in XY females and 67.2±10.1% in XY males, p<0.01). Infarct size was also markedly larger in XX mice than XY (52.4±4.7% in female-XX and 49.4±7.6% in male-XX vs. 33.2±5.6% in female-XY and 30.5±5.5% in male-XY, p<0.05). In XY* mice, functional recovery of mice with two copies of the X chromosome was significantly lower than mice with a single copy(recovery of RPP=34.0±10.3% XX females and 28.0±12.1% in XXY males vs. 60.3±13.5% in XO females and 60.5±13.8% in XO males, p<0.05). Infarct size was also markedly larger in mice with two X chromosomes (41.4±8.9% in XX females and 46.3±9.5% in XXY males) than mice with one X chromosome (23.7±3.9% in XO females and 26.6±6.9% in XO males, p<0.05). Conclusion: Irrespective of gonadal sex, the number of X chromosomes in gonadectomized mice plays a key role in susceptibility to myocardial I/R injury regardless of the presence or absence of the Y chromosome.