YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload
The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-03-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI150595 |
| _version_ | 1811329321033269248 |
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| author | Toshihide Kashihara Risa Mukai Shin-ichi Oka Peiyong Zhai Yasuki Nakada Zhi Yang Wataru Mizushima Tsutomu Nakahara Junco S. Warren Maha Abdellatif Junichi Sadoshima |
| author_facet | Toshihide Kashihara Risa Mukai Shin-ichi Oka Peiyong Zhai Yasuki Nakada Zhi Yang Wataru Mizushima Tsutomu Nakahara Junco S. Warren Maha Abdellatif Junichi Sadoshima |
| author_sort | Toshihide Kashihara |
| collection | DOAJ |
| description | The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect. |
| first_indexed | 2024-04-13T15:41:49Z |
| format | Article |
| id | doaj.art-2bede1f3f1824fc7aaf8eccc22265fe8 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-13T15:41:49Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-2bede1f3f1824fc7aaf8eccc22265fe82022-12-22T02:41:08ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-03-011326YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overloadToshihide KashiharaRisa MukaiShin-ichi OkaPeiyong ZhaiYasuki NakadaZhi YangWataru MizushimaTsutomu NakaharaJunco S. WarrenMaha AbdellatifJunichi SadoshimaThe heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.https://doi.org/10.1172/JCI150595Cardiology |
| spellingShingle | Toshihide Kashihara Risa Mukai Shin-ichi Oka Peiyong Zhai Yasuki Nakada Zhi Yang Wataru Mizushima Tsutomu Nakahara Junco S. Warren Maha Abdellatif Junichi Sadoshima YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload The Journal of Clinical Investigation Cardiology |
| title | YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| title_full | YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| title_fullStr | YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| title_full_unstemmed | YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| title_short | YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| title_sort | yap mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload |
| topic | Cardiology |
| url | https://doi.org/10.1172/JCI150595 |
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