title: Mechanisms of sex differences in TNFR2-mediated cardioprotection.
abstract: BACKGROUND
  TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males.
  
  
  RESULTS
  Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females.
  
  
  CONCLUSIONS
  Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.
authors.affiliation: Departments of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dmeldrum@iupui.edu
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crisostomo
authors.forename: Troy A
authors.initials: TA
authors.lastname: Markel
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D017209:Apoptosis; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000378:metabolism*; D020127:Recovery of Function; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; D020928:Mitogen-Activated Protein Kinases