Journal article
High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4
Molecular medicine (Cambridge, Mass.), Vol.18(1), pp.1509-1518
12/20/2012
DOI: 10.2119/molmed.2012.00283
PMCID: PMC3576475
PMID: 23269975
Abstract
Survival rates for patients with pulmonary hypertension (PH) remain low, and our understanding of the mechanisms involved are incomplete. Here we show in a mouse model of chronic hypoxia (CH)-induced PH that the nuclear protein and damage-associate molecular pattern molecule (DAMP) high mobility group box 1 (HMGB1) contributes to PH via a Toll-like receptor 4 (TLR4)-dependent mechanism. We demonstrate extranuclear HMGB1 in pulmonary vascular lesions and increased serum HMGB1 in patients with idiopathic pulmonary arterial hypertension. The increase in circulating HMGB1 correlated with mean pulmonary artery pressure. In mice, we similarly detected the translocation and release of HMGB1 after exposure to CH. HMGB1-neutralizing antibody attenuated the development of CH-induced PH, as assessed by measurement of right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling and endothelial activation and inflammation. Genetic deletion of the pattern recognition receptor TLR4, but not the receptor for advanced glycation end products, likewise attenuated CH-induced PH. Finally, daily treatment of mice with recombinant human HMGB1 exacerbated CH-induced PH in wild-type (WT) but not
Tlr4
−/−
mice. These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH.
Details
- Title: Subtitle
- High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4
- Creators
- Eileen M Bauer - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaRichard Shapiro - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaHan Zheng - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaFerhaan Ahmad - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaDavid Ishizawar - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaSuzy A Comhair - Department of Pathobiology, Lerner Research Institute, and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of AmericaSerpil C Erzurum - Department of Pathobiology, Lerner Research Institute, and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of AmericaTimothy R Billiar - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaPhilip M Bauer - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
- Resource Type
- Journal article
- Publication Details
- Molecular medicine (Cambridge, Mass.), Vol.18(1), pp.1509-1518
- DOI
- 10.2119/molmed.2012.00283
- PMID
- 23269975
- PMCID
- PMC3576475
- NLM abbreviation
- Mol Med
- ISSN
- 1076-1551
- eISSN
- 1528-3658
- Publisher
- ScholarOne
- Language
- English
- Date published
- 12/20/2012
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984025684902771
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