ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction
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.
Authors
- Lizhuo Ai (ORCID: https://orcid.org/0000-0001-5449-9888)
- Qin Zhang (ORCID: https://orcid.org/0000-0002-5664-5823)
- Kaichao Pan
- James K. Liao (ORCID: https://orcid.org/0000-0001-9679-4252)
- Qiong Zhao (ORCID: https://orcid.org/0000-0003-4924-157X)
- Albert Sitikov
- Willard W. Sharp (ORCID: https://orcid.org/0000-0002-7175-3523)
- David Wu (ORCID: https://orcid.org/0000-0001-9571-2622)
- Karim Ullah (ORCID: https://orcid.org/0000-0003-0007-3448)
- Zainab Humayun (ORCID: https://orcid.org/0009-0007-6908-6008)
- Lin Piao (ORCID: https://orcid.org/0000-0002-2097-8335)
- Qiaozhu Su (ORCID: https://orcid.org/0000-0001-8434-1408)
- Yun Fang (ORCID: https://orcid.org/0000-0003-4597-3095)
- Yan Li (ORCID: https://orcid.org/0000-0002-8259-2470)
- Rongxue Wu (ORCID: https://orcid.org/0000-0003-4857-4655)
- Lifeng Liu (ORCID: https://orcid.org/0000-0002-6363-3433)
Institutions
- Queen's University Belfast (GB)
- University of Arizona (US)
- University of Chicago (US)
- Alaska Heart and Vascular Institute (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-03-15
- DOI
- https://doi.org/10.1038/s42003-025-07753-1
- Citations
- 4
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.75
Funders
- Diabetes Research and Training Center
- National Heart, Lung, and Blood Institute