NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway

Exp Cell Res. 2023 Oct 15;431(2):113755. doi: 10.1016/j.yexcr.2023.113755. Epub 2023 Aug 14.


Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.

Keywords: Endothelial cells; Hypoxic pulmonary hypertension; NLRC3; Pulmonary arterial smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Humans
  • Hypertension, Pulmonary* / genetics
  • Hypertension, Pulmonary* / metabolism
  • Hypoxia / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Myocytes, Smooth Muscle / metabolism
  • NF-kappa B / metabolism
  • Pulmonary Artery / metabolism
  • Rats
  • Vascular Remodeling / genetics


  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • NLRC3 protein, human
  • NLRC3 protein, mouse
  • RELA protein, human
  • HIF1A protein, human

Supplementary concepts

  • Pulmonary edema of mountaineers