Hypoxia-induced activation of specific members of the NF-kB family and its relevance to pulmonary vascular remodeling

Hardik Patel, Nahla Zaghloul, Ki Lin, Shu Fang Liu, Edmund J. Miller, Mohamed Ahmed

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background and objective Pulmonary Hypertension (pH) is a chronic progressive disease. Endothelial cells (EC) play a central and critical role in the initiation and progression of pH. The NF-κB family (NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and C-Rel) regulates a wide array of genes involved in inflammatory responses, cell proliferation, and survival. The involvement of specific NF-κB family members in the pathogenesis of hypoxia-induced pH remains to be determined. The objective of this study was to assess the specific role of individual NF-κB family members in mediating endothelial cell responses to hypoxia and its downstream effect on smooth muscle cell proliferation. Methods and results NF-κB family members’ expression were selectively reduced by siRNA in human pulmonary microvascular endothelial cells. Cells were then exposed to hypoxia (1%) for 24 h. Endothelin1, ICAM1 gene expression and Stat1 and Stat3 phosphorylation were assessed. Smooth muscle cells (SMC) proliferation was assessed by culturing them with EC conditioned media. Reduction of either NF-κB2 or RelA in EC, led to a significant decrease in Endothelin1 and ICAM1 gene expression. C-Rel knockdown resulted in a significant increase in phosphorylated STAT1; both C-Rel and RelA knockdown significantly decreased phosphorylated STAT3 in EC. There was a significant reduction in SMC proliferation, and AKT/ERK phosphorylation in SMC, when cultured in RelA knockdown, EC conditioned media. Conclusion RelA in EC plays crucial role in hypoxia induced vascular remodeling and development of pH. Targeting RelA in EC alleviates SMC proliferation as well as inflammation related processes.

Original languageEnglish (US)
Pages (from-to)141-147
Number of pages7
JournalInternational Journal of Biochemistry and Cell Biology
Volume92
DOIs
StatePublished - Nov 2017
Externally publishedYes

Keywords

  • Endothelial cells
  • NF-kappa B
  • Pulmonary hypertension
  • Smooth muscle myocytes proliferation
  • Vascular remodeling

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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