ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction
Abstract 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 endo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07753-1 |
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| _version_ | 1850039452088401920 |
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| author | Karim Ullah Lizhuo Ai Yan Li Lifeng Liu Qin Zhang Kaichao Pan Zainab Humayun Lin Piao Albert Sitikov Qiong Zhao Qiaozhu Su Willard Sharp Yun Fang David Wu James K. Liao Rongxue Wu |
| author_facet | Karim Ullah Lizhuo Ai Yan Li Lifeng Liu Qin Zhang Kaichao Pan Zainab Humayun Lin Piao Albert Sitikov Qiong Zhao Qiaozhu Su Willard Sharp Yun Fang David Wu James K. Liao Rongxue Wu |
| author_sort | Karim Ullah |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-0b4f98e204e64a2aa772102ec44ab0e7 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-0b4f98e204e64a2aa772102ec44ab0e72025-08-20T02:56:20ZengNature PortfolioCommunications Biology2399-36422025-03-018111810.1038/s42003-025-07753-1ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarctionKarim Ullah0Lizhuo Ai1Yan Li2Lifeng Liu3Qin Zhang4Kaichao Pan5Zainab Humayun6Lin Piao7Albert Sitikov8Qiong Zhao9Qiaozhu Su10Willard Sharp11Yun Fang12David Wu13James K. Liao14Rongxue Wu15Section of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoDepartment of Human Genetics, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoEmergency Medicine, Department of Medicine, University of ChicagoSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoDivision of Cardiology, Department of Medicine, Inova Heart and Vascular InstituteInstitute for Global Food Security, School of Biological Sciences, Queen’s University BelfastEmergency Medicine, Department of Medicine, University of ChicagoSection of Pulmonary and Critical Care, Department of Medicine, University of ChicagoSection of Pulmonary and Critical Care, Department of Medicine, University of ChicagoDepartment of Medicine, University of ArizonaSection of Cardiology,, Biological Sciences Division, Department of Medicine, University of ChicagoAbstract 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.https://doi.org/10.1038/s42003-025-07753-1 |
| spellingShingle | Karim Ullah Lizhuo Ai Yan Li Lifeng Liu Qin Zhang Kaichao Pan Zainab Humayun Lin Piao Albert Sitikov Qiong Zhao Qiaozhu Su Willard Sharp Yun Fang David Wu James K. Liao Rongxue Wu ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction Communications Biology |
| title | ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction |
| title_full | ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction |
| title_fullStr | ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction |
| title_full_unstemmed | ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction |
| title_short | ARNT-dependent HIF-2α signaling protects cardiac microvascular barrier integrity and heart function post-myocardial infarction |
| title_sort | arnt dependent hif 2α signaling protects cardiac microvascular barrier integrity and heart function post myocardial infarction |
| url | https://doi.org/10.1038/s42003-025-07753-1 |
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