Abstract 787: Tumor Necrosis Factor-α is Toxic via Receptor 1 and Protective via Receptor 2 in a Murine Model of Myocardial Infarction
Introduction: Tumor necrosis factor (TNF)-α induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-α in cardiovascular diseases. Although TNF-α has been shown to initiate its biological effects by binding to two distinct receptors (R1 and R2), little is known about the role of R2 in myocardial infarction (MI).
Hypothesis: TNF-α is toxic via R1 and protective via R2 in cardiac dysfunction and remodeling after MI.
Methods: We created MI in R1 knockout (KO), R2 KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 weeks after the ligation.
Results: KO of R1 but not R2 significantly improved the survival after MI: 12 of 58 R1 KO (20.7 %), 28 of 61 R2 KO (45.9 %), and 25 of 60 WT mice (41.7 %) died within 4 weeks after MI. Infarct size was not different among WT, R1 KO, and R2 KO mice. KO of R1 significantly ameliorated contractile dysfunction after MI, while R2 KO significantly exaggerated ventricular dilatation and contractile dysfunction by echocardiography. Compared with WT mice, LV dP/dtmax was significantly higher in R1 KO (5581 ± 715 mmHg/s vs. 5051 ± 731 mmHg/s, p < 0.05) and significantly lower in R2 KO mice (4450 ± 603 mmHg/s vs. 5051 ± 731 mmHg/s, p < 0.05). Myocyte hypertrophy and interstitial fibrosis in non-infarct myocardium was exacerbated in R2 KO but not in R1 KO mice. Expression of TNF-α, which was significantly up-regulated in infarct as well as in non-infarct myocardium, was not affected by R1 or R2 KO. Meanwhile, expression of R1, which was not affected by MI but null in R1 KO, was significantly up-regulated in R2 KO/MI mice. In contrast, expression of R2, which was significantly up-regulated by MI and null in R2 KO, was unaffected by R1 KO.
Conclusions: In a murine model of MI, inhibition of TNF R1-mediated pathways attenuates ventricular dysfunction and improves the survival. In contrast, inhibition of TNF R2-mediated pathways exacerbates ventricular dysfunction and remodeling with up-regulation of R1. Since these results support our hypothesis, selective blockade of TNF R1 may be desirable for therapeutic interventions in cardiovascular diseases.