Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia.
BACKGROUND
Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue after ischemia and reperfusion (I/R). TNF contributes to postischemic myocardial dysfunction and induces proinflammatory signaling, which may be mediated by the 55-kDa TNF receptor (TNFR1). In humans, there is a direct correlation between functional capacity, survival, and circulating TNF levels. Although decreasing the TNF level in animals was beneficial after myocardial ischemia, simply decreasing the bioavailability of TNF in humans with heart failure was not beneficial. This led to the important appreciation that TNF may have beneficial or deleterious effects in the heart, depending on which of its receptors is activated. Females have a lower incidence of heart failure and a higher heart failure survival than males. We hypothesized that TNFR1 signaling resistance occurs in the female myocardium during ischemia.


RESULTS
Hearts from male and female TNFR1-knockout and wild-type (WT) mice were subjected to I/R. Female WT mice had better postischemic recovery than did male WT mice, an effect that appeared to be due to TNFR1 signaling resistance in females. Female WT mice had less myocardial depression after TNF infusion despite equivalent TNFR1 expression. Interestingly, TNFR1 ablation improved postischemic myocardial function, decreased activation of p38 mitogen-activated protein kinase, and reduced expression of interleukins-1beta and -6 in males but not in females. Furthermore, WT females expressed more of the suppressor of cytokine signaling protein 3 after I/R, which may in part explain TNFR1 signaling resistance in the female myocardium.


CONCLUSIONS
This study demonstrates that sex differences exist in myocardial TNF signaling by TNFR1 after I/R.
Wang
Meijing
M
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Tsai
Ben M
BM
Crisostomo
Paul R
PR
Meldrum
Daniel R
DR
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D006321:Heart / Q000503:physiopathology*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000032:analysis; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D048051:p38 Mitogen-Activated Protein Kinases