Biological Sciences Division
Published March 15, 2025 | Version v1
Journal article Open

ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction

Creators

  • 1. University of Chicago
  • 2. Inova Heart and Vascular Institute
  • 3. Queen's University Belfast
  • 4. University of Arizona

Description

Myocardial infarction (MI) compromises the cardiac microvascular endothelial barrier, increasing leakage and inflammation. HIF2α, predominantly expressed in cardiac endothelial cells during ischemia, has an unclear role in barrier function during MI. Here, we show that inducible, adult endothelial-specific deletion of Hif2α in mice leads to increased mortality, cardiac leakage, inflammation, reduced heart function, and adverse remodeling after MI. In parallel, human cardiac microvascular endothelial cells (HCMVECs) lacking HIF2α display impaired barrier integrity, reduced tight-junction proteins, increased cell death, and elevated IL-6 levels, effects that are alleviated by overexpressing ARNT, a key partner of HIF2α under hypoxic conditions. Interestingly, ARNT, but not HIF2α, directly binds the IL-6 promoter to suppress its expression. These findings suggest the HIF2α/ARNT axis as a protective mechanism in heart failure post-MI and identify potential therapeutic targets to support cardiac function.

Data availability

All data supporting the findings of this study are available from the corresponding author upon request. The RNA sequencing data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE233064. Additionally, all source data underlying the graphs and charts presented in the main figures are provided in Supplementary Data.

Files

ARNT-dependent-HIF-2α-signaling-protects-cardiac-microvascular-barrier-integrity-and-heart-function-post-myocardial-infarction.pdf

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Additional details

Identifiers

DOI
10.1038/s42003-025-07753-1
Other
oai:uchicago.tind.io:14743

Funding

National Institutes of Health
1R01HL140114-01A1
National Institutes of Health
P30 DK020595
National Institutes of Health
UL1 TR000430
National Institutes of Health
R01HL133675
National Institutes of Health
R01HL169679

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Medicine