Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1
The transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion (Hif1aloxP/...
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| Format: | Article |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.970415/full |
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| author | Ka Lin Heck-Swain Jiwen Li Jiwen Li Wei Ruan Wei Ruan Xiaoyi Yuan Yanyu Wang Michael Koeppen Holger K. Eltzschig |
| author_facet | Ka Lin Heck-Swain Jiwen Li Jiwen Li Wei Ruan Wei Ruan Xiaoyi Yuan Yanyu Wang Michael Koeppen Holger K. Eltzschig |
| author_sort | Ka Lin Heck-Swain |
| collection | DOAJ |
| description | The transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion (Hif1aloxP/loxP UbiquitinCre+) have exaggerated myocardial injury during in situ ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific Hif1a deletion (Hif1aloxP/loxP LysM Cre+). In contrast, mice with myocardial specific (Hif1aloxP/loxP Myosin Cre+), or vascular Hif1a deletion (Hif1aloxP/loxP VEcadherin Cre+) experienced similar levels of injury as controls. Subsequent studies using adoptive transfer of Hif1a-deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. On the contrary, the adoptive transfer of PMNs treated ex vivo with the hypoxia inducible factor (HIF) stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Furthermore, DMOG-mediated cardioprotection was abolished in Hif1aloxP/loxP LysM Cre+ mice, but not in Hif2aloxP/loxP LysM Cre+ mice. Finally, studies of PMN-dependent HIF1A target genes implicated the neuronal guidance molecule netrin-1 in mediating the cardioprotective effects of myeloid HIF1A. Taken together, the present studies identified a functional role for myeloid-expressed HIF1A in providing cardioprotection during ischemia and reperfusion injury, which is mediated, at least in part, by the induction of the netrin-1 neuronal guidance molecule in neutrophils. |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-12T04:23:05Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-409a2b8862ef429583da002b892ec1492022-12-22T03:48:09ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-09-01910.3389/fcvm.2022.970415970415Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1Ka Lin Heck-Swain0Jiwen Li1Jiwen Li2Wei Ruan3Wei Ruan4Xiaoyi Yuan5Yanyu Wang6Michael Koeppen7Holger K. Eltzschig8Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard Karls University of Tübingen, Tübingen, GermanyDepartment of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard Karls University of Tübingen, Tübingen, GermanyDepartment of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesThe transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion (Hif1aloxP/loxP UbiquitinCre+) have exaggerated myocardial injury during in situ ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific Hif1a deletion (Hif1aloxP/loxP LysM Cre+). In contrast, mice with myocardial specific (Hif1aloxP/loxP Myosin Cre+), or vascular Hif1a deletion (Hif1aloxP/loxP VEcadherin Cre+) experienced similar levels of injury as controls. Subsequent studies using adoptive transfer of Hif1a-deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. On the contrary, the adoptive transfer of PMNs treated ex vivo with the hypoxia inducible factor (HIF) stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Furthermore, DMOG-mediated cardioprotection was abolished in Hif1aloxP/loxP LysM Cre+ mice, but not in Hif2aloxP/loxP LysM Cre+ mice. Finally, studies of PMN-dependent HIF1A target genes implicated the neuronal guidance molecule netrin-1 in mediating the cardioprotective effects of myeloid HIF1A. Taken together, the present studies identified a functional role for myeloid-expressed HIF1A in providing cardioprotection during ischemia and reperfusion injury, which is mediated, at least in part, by the induction of the netrin-1 neuronal guidance molecule in neutrophils.https://www.frontiersin.org/articles/10.3389/fcvm.2022.970415/fullhypoxiamyocardial infarctionpolymorphonuclear neutrophil (PMN)reperfusionhearthypoxia inducible factor (HIF) |
| spellingShingle | Ka Lin Heck-Swain Jiwen Li Jiwen Li Wei Ruan Wei Ruan Xiaoyi Yuan Yanyu Wang Michael Koeppen Holger K. Eltzschig Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 Frontiers in Cardiovascular Medicine hypoxia myocardial infarction polymorphonuclear neutrophil (PMN) reperfusion heart hypoxia inducible factor (HIF) |
| title | Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 |
| title_full | Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 |
| title_fullStr | Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 |
| title_full_unstemmed | Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 |
| title_short | Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1 |
| title_sort | myeloid hypoxia inducible factor hif1a provides cardio protection during ischemia and reperfusion via induction of netrin 1 |
| topic | hypoxia myocardial infarction polymorphonuclear neutrophil (PMN) reperfusion heart hypoxia inducible factor (HIF) |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.970415/full |
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