Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension

Roger A. Johns, Eiki Takimoto, Lucas W. Meuchel, Esra Elsaigh, Ailan Zhang, Nicola M. Heller, Gregg L. Semenza, Kazuyo Kegan

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Objective-Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results-In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/-) mice. HIMF-induced PH was significantly diminished in HIF-1α+/- mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions-Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

Original languageEnglish (US)
Pages (from-to)134-144
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number1
StatePublished - Jan 1 2016


  • hypertension
  • hypoxia-inducible factor 1
  • interleukins
  • macrophages
  • pulmonary
  • resistin-like molecule

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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