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(Circulation. 2006;114:I-282 – I-289.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Tumor Necrosis Factor Receptor 1 Signaling Resistance in the Female Myocardium During Ischemia

Meijing Wang, MD, MS; Ben M. Tsai, MD; Paul R. Crisostomo, MD; Daniel R. Meldrum, MD

From the Departments of Surgery (M.W., B.M.T., P.R.C., D.R.M.) and Cellular and Integrative Physiology (D.R.M.) and the Indiana Center for Immunobiology (D.R.M.), Indiana University School of Medicine, Indianapolis, Ind.

Correspondence to Daniel R. Meldrum, MD, 545 Barnhill Dr, Emerson 215, Indianapolis, IN 46202. E-mail dmeldrum{at}iupui.edu

Background— Tumor necrosis factor- (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.

Methods and 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-1ß 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.

Key Words: ischemia • receptors • sex