Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1
Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and dis...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.024854 |
| _version_ | 1797810174915772416 |
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| author | Le Ni Bowen Lin Lingjie Hu Ruoyu Zhang Fengmei Fu Meiting Shen Jian Yang Dan Shi |
| author_facet | Le Ni Bowen Lin Lingjie Hu Ruoyu Zhang Fengmei Fu Meiting Shen Jian Yang Dan Shi |
| author_sort | Le Ni |
| collection | DOAJ |
| description | Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies. |
| first_indexed | 2024-03-13T07:04:14Z |
| format | Article |
| id | doaj.art-3b17730783af4c75a8fdece77de14668 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-13T07:04:14Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-3b17730783af4c75a8fdece77de146682023-06-06T12:11:52ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-06-01111110.1161/JAHA.121.024854Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1Le Ni0Bowen Lin1Lingjie Hu2Ruoyu Zhang3Fengmei Fu4Meiting Shen5Jian Yang6Dan Shi7Department of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaDepartment of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaDepartment of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaJinzhou Medical University Liaoning ChinaJinzhou Medical University Liaoning ChinaDepartment of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaDepartment of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaDepartment of Cardiology Shanghai East HospitalTongji University School of Medicine Shanghai ChinaBackground Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.https://www.ahajournals.org/doi/10.1161/JAHA.121.024854heart failureprotein kinasepyruvate kinase M2rho familysmall GTP binding protein |
| spellingShingle | Le Ni Bowen Lin Lingjie Hu Ruoyu Zhang Fengmei Fu Meiting Shen Jian Yang Dan Shi Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease heart failure protein kinase pyruvate kinase M2 rho family small GTP binding protein |
| title | Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 |
| title_full | Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 |
| title_fullStr | Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 |
| title_full_unstemmed | Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 |
| title_short | Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1 |
| title_sort | pyruvate kinase m2 protects heart from pressure overload induced heart failure by phosphorylating rac1 |
| topic | heart failure protein kinase pyruvate kinase M2 rho family small GTP binding protein |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.024854 |
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