2. Academic Validation
  3. HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling

HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling

  • Vascul Pharmacol. 2019 Jun;117:35-44. doi: 10.1016/j.vph.2018.12.006.
Jin Wang 1,  Xiao-Ting Tian 2,  Zhouyf Peng 3,  Wen-Qun Li 4,  Yuan-Yuan Cao 2,  Ying Li 5,  Xiao-Hui Li 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China; Department of Clinical Pharmacy, First People's Hospital of Huaihua, Huaihua 418000, China.
  • 2 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China.
  • 3 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
  • 4 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
  • 5 Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China.
  • 6 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China. Electronic address: xiaohuili@csu.edu.cn.
PMID: 30610955 DOI: 10.1016/j.vph.2018.12.006
Abstract

High mobility group box 1 (HMGB1), a critical nonclassical inflammatory cytokine, has been found up-regulated in patients with idiopathic pulmonary arterial hypertension (IPAH), but its role in vascular remodeling of pulmonary hypertension (PH) is still unknown. In present study, we demonstrated that the plasma level of inflammatory cytokine including HMGB1, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were elevated in hypoxia-induced pulmonary hypertension rats model. Moreover, expressions of HMGB1 and Toll like receptor-4 (TLR4) in pulmonary arteries were obviously up-regulated accompanied with down-regulation of bone morphogenetic protein receptor 2 (BMPR2) signaling, characterized by decline of phosphorylated Smad1/5/8 (p-Smsd1/5/8) and inhibitor of differention 1 (Id1) expression. In cultured primary pulmonary arterial smooth muscle cells (PASMCs), we found that HMGB1 incubation significantly promoted proliferation and migration of PASMCs, down-regulated p-Smsd1/5/8 and Id1 expression, which can be abrogated by HMGB1 inhibitors saquinavir, glycyrrhizn and TLR4 inhibitors TAK-242. Furthermore, saquinavir, glycyrrhizn and TAK-242 treatment significantly attenuated the development of PH in rats by recovering homodynamic parameters, pulmonary vascular remodeling and BMPR2 signaling pathway. In summary, our results suggest that HMGB1/TLR4 signaling promotes hypoxia-induced pulmonary hypertension via suppressing BMPR2 signaling.

Keywords

BMPR2; HMGB1; Inflammation; Pulmonary hypertension; TLR4.

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