Abstract 216: Sex Chromosome Protection Again Myocardial Ischemia/reperfusiong Injury In Mice: One X Is Better Than Two

Abstract

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 the I/R injury model have been attributed to sex hormones. Here we used a unique mouse model (XY*) to investigate the role of sex chromosomes on cardiac I/R injury. The XY* model produces the equivalent of XX and XO gonadal females, and XY and XXY gonadal males. A comparison between mice with one X chromosome (XO or XY) to those with two X chromosomes (XX or XXY) reveals an effect of X chromosome number, whereas comparing mice with a Y chromosome (XY, XXY) with those without Y (XO, XX) shows the effect of presence/absence of the Y chromosome. Four to six weeks before the experiment, mice were gonadectomized (GDX) to eliminate the effects of gonadal hormones. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. Hemodynamic parameters were continuously recorded with a catheter (1.4F Millar SPR-671) connected to a pressure transducer (Power Lab, ADInstruments). At the end of reperfusion, the hearts were cut into four transverse slices and myocardial necrosis was assessed by measurement of the infarct size using triphenyltetrazolium chloride (TTC) staining. The cardiac function was similar among all 4 groups of XY* mice before ischemia. However, postischemic functional recovery of mice with two copies of the X chromosome was significantly lower than mice with a single copy, irrespective of gonadal sex. Rate pressure product (RPP) recovery was markedly lower in XX gonadal females (34.0±10.3%, n=6) and XXY gonadal males (28.0±12.1%, n=5) compared to XO females (60.3±13.5%, n=4) and XO males (60.5±13.8%, n=5, p<0.05). Infarct size was also markedly larger in mice with two X chromosomes (41.4±8.9% in XX gonadal females (n=6) and 46.3±9.5% in XXY gonadal males (n=5)) than mice with one X chromosome (23.7±3.9% in XO females, n=4 and 26.6±6.9% in XO males, n=5, p<0.05). In conclusion, the number of X chromosomes in gonadectomized mice plays a key role in susceptibility to myocardial ischemia/reperfusion injury regardless of the presence or absence of the Y chromosome.