Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension

Hiroshi Kojima, Tomotake Tokunou, Yusuke Takahara, Kenji Sunagawa, Yoshitaka Hirooka, Toshihiro Ichiki, Hiroyuki Tsutsui

Research output: Contribution to journalArticle

Abstract

Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF-1α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid-specific HIF-1α knockout (MyeHIF1KO) mice by using Cre-lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from MyeHIF1KO and control mice were used for western blotting, RT-qPCR, chemotaxis assay, and ATP assay. MyeHIF1KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF-1α-deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein-1 and a decrease in intracellular ATP levels. These results indicate that HIF-1α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid-specific HIF-1α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.

Original languageEnglish
Article numbere14025
JournalPhysiological Reports
Volume7
Issue number7
DOIs
Publication statusPublished - Apr 1 2019

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Hypoxia-Inducible Factor 1
Pulmonary Hypertension
Knockout Mice
Lung
Macrophages
Vasoconstriction
Adenosine Triphosphate
Weights and Measures
Chemokine CCL2
Erythropoiesis
Peritoneal Macrophages
Ventricular Pressure
Chemotaxis
Myeloid Cells
Pulmonary Artery
Heart Ventricles
Blood Vessels
Hypoxia
Transcription Factors
Western Blotting

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension. / Kojima, Hiroshi; Tokunou, Tomotake; Takahara, Yusuke; Sunagawa, Kenji; Hirooka, Yoshitaka; Ichiki, Toshihiro; Tsutsui, Hiroyuki.

In: Physiological Reports, Vol. 7, No. 7, e14025, 01.04.2019.

Research output: Contribution to journalArticle

Kojima, Hiroshi ; Tokunou, Tomotake ; Takahara, Yusuke ; Sunagawa, Kenji ; Hirooka, Yoshitaka ; Ichiki, Toshihiro ; Tsutsui, Hiroyuki. / Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension. In: Physiological Reports. 2019 ; Vol. 7, No. 7.
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