Divergent Tumor Necrosis Factor Receptor–Related Remodeling Responses in Heart Failure: Role of Nuclear Factor-κB and Inflammatory Activation

Abstract

Background— Although preclinical data suggested that tumor necrosis factor-α (TNF) neutralization in heart failure (HF) would be beneficial, clinical trials of TNF antagonists were paradoxically negative. We hypothesized that TNF induces opposing inflammatory and remodeling responses in HF that are TNF-receptor (TNFR) specific. Methods and Results— HF was induced in wild-type (WT), TNFR1 −/− , and TNFR2 −/− mice via coronary ligation. Compared with WT HF, 4-week postinfarction survival was significantly improved in both TNFR1 −/− and TNFR2 −/− HF. Compared with sham, WT HF hearts exhibited significant remodeling with robust activation of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1β, IL-6, and IL-10. Compared with WT HF, TNFR1 −/− HF exhibited (1) improved remodeling, hypertrophy, and contractile function; (2) less apoptosis; and (3) diminished NF-κB, p38 mitogen-activated protein kinase, and JNK2 activation and cytokine expression. In contrast, TNFR2 −/− HF showed exaggerated remodeling and hypertrophy, increased border zone fibrosis, augmented NF-κB and p38 mitogen-activated protein kinase activation, higher IL-1β and IL-6 gene expression, greater activated macrophages, and greater apoptosis. Oxidative stress and diastolic function were improved in both TNFR1 −/− and TNFR2 −/− HF. In H9c2 cardiomyocytes, sustained NF-κB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-κB activation. Conclusions— TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-κB, inflammation, and apoptosis in HF: TNFR1 exacerbates, whereas TNFR2 ameliorates, these events. However, signaling through both receptors is required to induce diastolic dysfunction and oxidative stress. TNFR-specific effects in HF should be considered when therapeutic anti-TNF strategies are developed.