P151: Ablation of the stat3 gene worsens myocardial function and neutralizes gender differences in functional recovery following ischemia

Abstract

Background: Acute injuries result in the activation of the signal transducer and activator of transcription 3 (STAT3) pathway. Recent studies have shown that females have better myocardial functional recovery, TNFR1 signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) when compared to males. However, it is unknown whether STAT3 is responsible for gender differences in myocardial functional recovery following I/R. We hypothesized that STAT3 deficiency worsens myocardial function in both sexes and that STAT3 deficiency neutralizes gender differences in functional recovery, as well as STAT3 and p38 MAPK activation following acute I/R. Methods: Isolated mouse hearts from WT (n=8/gender) and STAT3-CFF (n=3/gender) of both genders were subjected to 20 min ischemia/60 min reperfusion, and +dP/dT, -dP/dT were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK (Western blot) following I/R. p<0.05=statistically significant (ANOVA and Tukey’s). Results: STATKO had significantly worse myocardial functional recovery in both genders (% recovered +dP/dt: Male 51.6+/-3.1% vs. 32.1+/-13.1%, Female 79.1+/-3.6% vs. 43.6+/-9.1%; -dP/dt: Male 52.2+/-3.3% vs. 28.9+/-12%, Female 75.2+/-4.1% vs. 38.6+/-10%). In addition, STAT3KO neutralized gender differences in myocardial function, which existed in WT mice. Interestingly, STAT3 deficiency decreased myocardial STAT3 activation, but increased myocardial p38 MAPK activation, in both sexes, but to a greater degree in females. Conclusion: STAT3 deficiency resulted in decreased recovery of myocardial function in both genders and neutralized gender differences in myocardial functional recovery following I/R. In addition, STAT3 deficiency resulted in decreased activation of myocardial STAT3 and increased activation of p38 MAPK following I/R. The post-I/R TNFR1 signaling resistance observed in females may be mediated by increased activation of STAT3.