Abstract 1566: Tumor Necrosis Factor Receptor 2 Signaling Protects Myocardial Function Following Ischemia In Females Via Stat3, Socs3 And Vegf
Introduction: Myocardial ischemia/reperfusion (I/R) increases local TNF production, which contributes to myocardial dysfunction; however, the mechanisms remain incompletely understood. Some investigations have shown that TNF may be protective and others have shown it to be injurious. Our previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression following acute I/R when compared to males. However, the effect of TNFR2 on gender differences in myocardial functional recovery following I/R is unknown. We hypothesized that
TNFR2 mediates myocardial protection from I/R through STAT3, SOCS3 and VEGF in both genders,
TNFR2 elicits greater protective signaling in females as compared to males.
Methods: Isolated male and female mouse hearts (Langendorff) from TNFR2 knockout (TNFR2 KO), TNFR1/2KO and wild type (WT) (n=3– 6/group) were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. Myocardial function (+/−dP/dt) was continuously monitored. After I/R, hearts were analyzed for STAT3, SOCS3 and VEGFa gene expression (RT real-time PCR), STAT3 activation (Western blot). Two-way ANOVA or student’s t-test, p<0.05 statistically significant.
Results: TNFR2 deficiency decreased post-ischemic recovery of +/−dP/dt in both genders, but with greater effect on females. This deleterious effect of TNFR2KO was associated with a decrease in gene expression of VEGFa to 38%, STAT3 to 51% and SOCS3 to 36% in female TNFR2KO hearts, but without significant change in males. Additionally, TNFR1/2 KO decreased myocardial function in female hearts, but not in males. Interestingly, TNFR1/2 deficiency increased gene expression of VEGFa by 37%, SOCS3 by 30% in males, but decreased VEGFa by 48%, STAT3 by 45% and SOCS3 by 49% in females. Moreover, STAT3 activation was decreased in female TNFR2KO and TNFR1/2KO hearts.
Conclusions: TNFR2 mediates myocardial protection through VEGF, STAT3 and SOCS3 following I/R in both genders, but with a relatively greater benefit of TNFR2 signaling observed in females. These data expand upon gender-based TNF signaling in myocardium, which may in part explain certain clinical differences with important therapeutic implications.