Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.
Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon...
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Public Library of Science (PLoS)
2013-09-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001666&type=printable |
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| author | Ross A Breckenridge Izabela Piotrowska Keat-Eng Ng Timothy J Ragan James A West Surendra Kotecha Norma Towers Michael Bennett Petra C Kienesberger Ryszard T Smolenski Hillary K Siddall John L Offer Mihaela M Mocanu Derek M Yelon Jason R B Dyck Jules L Griffin Andrey Y Abramov Alex P Gould Timothy J Mohun |
| author_facet | Ross A Breckenridge Izabela Piotrowska Keat-Eng Ng Timothy J Ragan James A West Surendra Kotecha Norma Towers Michael Bennett Petra C Kienesberger Ryszard T Smolenski Hillary K Siddall John L Offer Mihaela M Mocanu Derek M Yelon Jason R B Dyck Jules L Griffin Andrey Y Abramov Alex P Gould Timothy J Mohun |
| author_sort | Ross A Breckenridge |
| collection | DOAJ |
| description | Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery. |
| format | Article |
| id | doaj-art-c94bc252bb4048fdb56691e64de2627d |
| institution | DOAJ |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2013-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-c94bc252bb4048fdb56691e64de2627d2025-08-20T03:10:02ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852013-09-01119e100166610.1371/journal.pbio.1001666Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.Ross A BreckenridgeIzabela PiotrowskaKeat-Eng NgTimothy J RaganJames A WestSurendra KotechaNorma TowersMichael BennettPetra C KienesbergerRyszard T SmolenskiHillary K SiddallJohn L OfferMihaela M MocanuDerek M YelonJason R B DyckJules L GriffinAndrey Y AbramovAlex P GouldTimothy J MohunCardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001666&type=printable |
| spellingShingle | Ross A Breckenridge Izabela Piotrowska Keat-Eng Ng Timothy J Ragan James A West Surendra Kotecha Norma Towers Michael Bennett Petra C Kienesberger Ryszard T Smolenski Hillary K Siddall John L Offer Mihaela M Mocanu Derek M Yelon Jason R B Dyck Jules L Griffin Andrey Y Abramov Alex P Gould Timothy J Mohun Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. PLoS Biology |
| title | Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. |
| title_full | Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. |
| title_fullStr | Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. |
| title_full_unstemmed | Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. |
| title_short | Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. |
| title_sort | hypoxic regulation of hand1 controls the fetal neonatal switch in cardiac metabolism |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001666&type=printable |
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