Sex differences in the mechanisms of myocardial ischemic injury and heart failure are poorly understood. Myocardial ischemia and reperfusion injury is a leading cause of heart failure and death in civilized countries. Tumor necrosis factor alpha (TNF) may play an important role in the development of heart failure. In humans, there is a direct correlation between functional capacity, survival, and circulating TNF levels. Although animal studies were very encouraging, clinical studies indicated that simply decreasing the bioavailability of TNF in heart failure patients was, on balance, detrimental. This led to the important appreciation that TNF itself may have beneficial or detrimental effects depending on which of its receptors (TNFR1 or TNFR2) is activated. Ablation of the TNFR1 gene blunts heart failure and improves survival, whereas ablation of the TNFR2 gene exacerbates heart failure and reduces survival. Differential TNF receptor activation may therefore be one explanation for clinical variation, but, in addition, differential intracellular signaling may have an important effect. Unbalancing TNF signaling to diminish its deleterious effects while enhancing its salutary effects may be an important new approach to the treatment of heart failure in females and males. One such approach is through suppression of cytokine signaling proteins (SOCS) disruption of TNFR1 signaling. Our preliminary data suggests that TNFR1 signaling resistance occurs in female myocardium which may be due to estrogen receptor mediated upregulation of SOCS protein production. After myocardial ischemia, TNF levels, ventricular dysfunction, and apoptosis are decreased in female myocardium. Depletion or blockade of estrogen abolished this effect. It remains unknown, however, whether gender based differences in TNFR1 signaling exist, and if so, the mechanisms by which they occur. We hypothesize that endogenous estrogen induces relative TNFR1 signaling resistance in female myocardium (human, mouse) during ischemia by estrogen receptor (alpha and/or beta) stimulation of SOCS protein (1, 2, and/or 3) crosstalk with TNFR1 signal transduction. To study this we propose the completion of the following specific aims: To determine whether; 1) TNFR1 signaling resistance occurs in female myocardium (human, mouse) during ischemia, and if so, whether resistance is mediated by endogenous estrogen activation of alpha or beta estrogen receptors; 2) TNFR1 signaling resistance in female myocardium is mediated by estrogen receptor stimulation of suppressor of cytokine signaling proteins (SOCS 1, 2, and/or 3) through STATS; 3) SOCS-3 mediates TNFR1 signaling resistance during myocardial ischemia; 4) SOCS-3 is required for estrogen induced TNFR1 signaling resistance. Female and male myocardium from the following study subjects will be tested: humans, wild type mice, STATS knockout mice, TNFR1 and TNFR2 knockout mice, and alpha and beta estrogen receptor knockout mice. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085595-02
Application #
7406868
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2007-04-16
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$467,297
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Manukyan, Mariuxi C; Weil, Brent R; Wang, Yue et al. (2011) Female stem cells are superior to males in preserving myocardial function following endotoxemia. Am J Physiol Regul Integr Comp Physiol 300:R1506-14
Weil, Brent R; Herrmann, Jeremy L; Abarbanell, Aaron M et al. (2011) Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia. Shock 36:235-41

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