Tags

Type your tag names separated by a space and hit enter

Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.
Circulation. 2009 Mar 17; 119(10):1386-97.Circ

Abstract

BACKGROUND

Although preclinical data suggested that tumor necrosis factor-alpha (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)-kappaB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1beta, 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-kappaB, 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-kappaB and p38 mitogen-activated protein kinase activation, higher IL-1beta 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-kappaB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-kappaB activation.

CONCLUSIONS

TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-kappaB, 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.

Authors+Show Affiliations

Institute Institute of Molecular Cardiology, Department of Medicine, University of Louisville and Louisville Veterans Affairs Medical Center, Louisville, KY 40202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19255345

Citation

Hamid, Tariq, et al. "Divergent Tumor Necrosis Factor Receptor-related Remodeling Responses in Heart Failure: Role of Nuclear factor-kappaB and Inflammatory Activation." Circulation, vol. 119, no. 10, 2009, pp. 1386-97.
Hamid T, Gu Y, Ortines RV, et al. Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation. 2009;119(10):1386-97.
Hamid, T., Gu, Y., Ortines, R. V., Bhattacharya, C., Wang, G., Xuan, Y. T., & Prabhu, S. D. (2009). Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation, 119(10), 1386-97. https://doi.org/10.1161/CIRCULATIONAHA.108.802918
Hamid T, et al. Divergent Tumor Necrosis Factor Receptor-related Remodeling Responses in Heart Failure: Role of Nuclear factor-kappaB and Inflammatory Activation. Circulation. 2009 Mar 17;119(10):1386-97. PubMed PMID: 19255345.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. AU - Hamid,Tariq, AU - Gu,Yan, AU - Ortines,Roger V, AU - Bhattacharya,Chhandashri, AU - Wang,Guangwu, AU - Xuan,Yu-Ting, AU - Prabhu,Sumanth D, Y1 - 2009/03/02/ PY - 2009/3/4/entrez PY - 2009/3/4/pubmed PY - 2009/4/17/medline SP - 1386 EP - 97 JF - Circulation JO - Circulation VL - 119 IS - 10 N2 - BACKGROUND: Although preclinical data suggested that tumor necrosis factor-alpha (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)-kappaB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1beta, 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-kappaB, 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-kappaB and p38 mitogen-activated protein kinase activation, higher IL-1beta 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-kappaB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-kappaB activation. CONCLUSIONS: TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-kappaB, 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/19255345/Divergent_tumor_necrosis_factor_receptor_related_remodeling_responses_in_heart_failure:_role_of_nuclear_factor_kappaB_and_inflammatory_activation_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.108.802918?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -