Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2a inhibitor

Zhiyu Dai, Maggie M. Zhu, Yi Peng, Narsa Machireddy, Colin E. Evans, Roberto Machado, Xianming Zhang, You Yang Zhao

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive vasoconstriction and obliterative vascular remodeling that leads to right heart failure (RHF) and death. Current therapies do not target vascular remodeling and RHF, and result in only modest improvement of morbidity and mortality. Objectives: To determine whether targeting HIF-2a (hypoxia-inducible factor-2a) with a HIF-2a-selective inhibitor could reverse PAH and RHF in various rodent PAH models. Methods: HIF-2a and its downstream genes were evaluated in lung samples and pulmonary arterial endothelial cells and smooth muscle cells from patients with idiopathic PAH as well as various rodent PAH models. A HIF-2a-selective inhibitor was used in human lung microvascular endothelial cells and in Egln1Tie2Cre mice, and in Sugen 5416/hypoxia- or monocrotalineexposed rats. MeasurementsandMainResults: Upregulation of HIF-2aand its target genes was observed in lung tissues and isolated pulmonary arterial endothelial cells from patients with idiopathicPAHand three distinct rodent PAH models. Pharmacological inhibition of HIF-2a by the HIF-2a translation inhibitor C76 (compound 76) reduced right ventricular systolic pressure and right ventricular hypertrophy and inhibited RHF and fibrosis as well as obliterative pulmonary vascular remodeling in Egln1Tie2Cre mice and Sugen 5416/hypoxiaPAHrats. Treatment of monocrotaline-exposed PAH rats with C76 also reversed right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling; prevented RHF; and promoted survival. Conclusions: These findings demonstrate that pharmacological inhibition of HIF-2a is a promising novel therapeutic strategy for the treatment of severe vascular remodeling and right heart failure in patients with PAH.

Original languageEnglish (US)
Pages (from-to)1423-1434
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume198
Issue number11
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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