Evidence map›Paper›PMID 31597444›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2019

HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension.

Qing Lin, Chunling Fan, Jose Gomez-Arroyo, Katrien Van Raemdonck, Lucas W Meuchel, John T Skinner, Allen D Everett, Xia Fang, Andrew A Macdonald, Kazuyo Yamaji-Kegan and 1 more

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In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed
3.1field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 53 citations in OpenAlex.

  1. The role of HMGB1 in vascular endothelial cells.Apoptosis : an international journal on programmed cell death · 2026
    Review
  2. Article
  3. HMGB1: a multifaceted mediator of cell death pathways in cardiovascular diseases.Apoptosis : an international journal on programmed cell death · 2025
    Review
  4. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension.International journal of molecular sciences · 2025
    Review
  5. Review
  6. Article
  7. Review
  8. Review
  9. [Quercetin improves pulmonary arterial hypertension in rats by regulating the HMGB1/RAGE/NF-κB pathway].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2023
    Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Endotyping COPD: hypoxia-inducible factor-2 as a molecular "switch" between the vascular and airway phenotypes?European respiratory review : an official journal of the European Respiratory Society · 2023
    Review
  15. Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.Journal of the American Heart Association · 2023
    Article
  16. Article
  17. Review
  18. Review
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 1 institution in 1 country.

Qing LinFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Chunling FanFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Jose Gomez-ArroyoFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Katrien Van RaemdonckFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Lucas W MeuchelFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
John T SkinnerFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Allen D EverettDivision of Pediatric Cardiology, Department of Pediatrics (A.D.E.), Johns Hopkins University School of Medicine, Baltimore, MD.
Xia FangFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Andrew A MacdonaldFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Kazuyo Yamaji-KeganFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Roger A JohnsFrom the Department of Anesthesiology and Critical Care Medicine (Q.L., C.F., J.G.-A., K.V.R., L.W.M., J.T.S., X.F., A.A.M., K.Y.-K., R.A.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
Johns Hopkins University · US

Funding

Targeting resitin and RELM-beta to treat pulmonary hypertensionUH3HL123827 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI JOHNS, ROGER A · 2016 to 2018
$4.9M
Targeting resitin and RELM-beta to treat pulmonary hypertensionUH2HL123827 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI JOHNS, ROGER A · 2014 to 2015
$3.1M
REGULATION OF NO SIGNALING IN PULMONARY VASCULATURER01HL039706 · NHLBI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI JOHNS, ROGER A · 1993 to 2006
$2.4M
Insulin Receptor Substrate Signaling in Pulmonary HypertensionR01HL135022 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI KEEGAN, ACHSAH D. · 2018 to 2022
$2.0M
DAMP Signaling Mediates HIMF-induced Pulmonary HypertensionR01HL138497 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI JOHNS, ROGER A · 2018 to 2021
$1.8M
Targeting resitin and RELM-beta to treat pulmonary hypertensionP50HL107182 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI JOHNS, ROGER A · 2011 to 2012
$983k
NHLBI NIH HHS P50 HL107182NHLBI NIH HHS R01 HL039706NHLBI NIH HHS R01 HL135022NHLBI NIH HHS R01 HL138497NHLBI NIH HHS UH2 HL123827NHLBI NIH HHS UH3 HL123827
6 · The paper itself

Abstract

objectiveHIMF (hypoxia-induced mitogenic factor; also known as FIZZ1 [found in inflammatory zone-1] or RELM [resistin-like molecule-α]) is an etiological factor of pulmonary hypertension (PH) in rodents, but its underlying mechanism is unclear. We investigated the immunomodulatory properties of HIMF signaling in PH pathogenesis. Approach and Results: Gene-modified mice that lacked HIMF (KO [knockout]) or overexpressed HIMF human homolog resistin (hResistin) were used for in vivo experiments. The pro-PH role of HIMF was verified in HIMF-KO mice exposed to chronic hypoxia or sugen/hypoxia. Mechanistically, HIMF/hResistin activation triggered the HMGB1 (high mobility group box 1) pathway and RAGE (receptor for advanced glycation end products) in pulmonary endothelial cells (ECs) of hypoxic mouse lungs in vivo and in human pulmonary microvascular ECs in vitro. Treatment with conditioned medium from hResistin-stimulated human pulmonary microvascular ECs induced an autophagic response, BMPR2 (bone morphogenetic protein receptor 2) defects, and subsequent apoptosis-resistant proliferation in human pulmonary artery (vascular) smooth muscle cells in an HMGB1-dependent manner. These effects were confirmed in ECs and smooth muscle cells isolated from pulmonary arteries of patients with idiopathic PH. HIMF/HMGB1/RAGE-mediated autophagy and BMPR2 impairment were also observed in pulmonary artery (vascular) smooth muscle cells of hypoxic mice, effects perhaps related to FoxO1 (forkhead box O1) dampening by HIMF. Experiments in EC-specific hResistin-overexpressing transgenic mice confirmed that EC-derived HMGB1 mediated the hResistin-driven pulmonary vascular remodeling and PH.

conclusionsIn HIMF-induced PH, HMGB1-RAGE signaling is pivotal for mediating EC-smooth muscle cell crosstalk. The humanized mouse data further support clinical implications for the HIMF/HMGB1 signaling axis and indicate that hResistin and its downstream pathway may constitute targets for the development of novel anti-PH therapeutics in humans.

Indexed as

Gene Expression RegulationAnimalsAutophagyCell LineDisease Models, AnimalEndothelial CellsFemaleHMGB1 ProteinHumansHypertension, PulmonaryIntercellular Signaling Peptides and ProteinsMaleMiceMice, Inbred C57BLMice, TransgenicMuscle, Smooth, VascularHMGB1 ProteinHMGB1 protein, mouseIntercellular Signaling Peptides and ProteinsRetnla protein, mouseanimalshumansmiceresistinrodentia

Identifiers

PMID31597444
PMCPMC6879859
OpenAlexW2980281125

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.