title: High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, United States of America.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bauer
authors.forename: Richard
authors.initials: R
authors.lastname: Shapiro
authors.forename: Han
authors.initials: H
authors.lastname: Zheng
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: David
authors.initials: D
authors.lastname: Ishizawar
authors.forename: Suzy A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Philip M
authors.initials: PM
authors.lastname: Bauer
mesh_terms: D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; D051197:Toll-Like Receptor 4