PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart-Reference-Cited by-同舟云学术

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart

Published:2021-08-31 Issue:9 Volume:144 Page:712-727
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Li Qinfeng¹²³,Li Chao³,Elnwasany Abdallah³,Sharma Gaurav⁴^ORCID,An Yu A.⁵^ORCID,Zhang Guangyu,Elhelaly Waleed M.³,Lin Jun¹²,Gong Yingchao¹²,Chen Guihao³,Wang Meihui¹²,Zhao Shangang⁵^ORCID,Dai Chongshan³,Smart Charles D.³^ORCID,Liu Juan⁶,Luo Xiang³,Deng Yingfeng⁵^ORCID,Tan Lin⁷,Lv Shuang-Jie⁸,Davidson Shawn M.⁹,Locasale Jason W.⁶,Lorenzi Philip L.⁷^ORCID,Malloy Craig R.⁴¹⁰¹¹,Gillette Thomas G.³,Vander Heiden Matthew G.⁹¹²^ORCID,Scherer Philipp E.⁵^ORCID,Szweda Luke I.³,Fu Guosheng¹²^ORCID,Wang Zhao V.³^ORCID

Affiliation:

1. Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China (Q.L., J.Lin, Y.G., M.W., G.F.).

2. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Zhejiang, China (Q.L., J.Lin, Y.G., M.W., G.F.).

3. Division of Cardiology, Department of Internal Medicine (Q.L., C.L., A.E., G.Z., W.M.E., G.C., C.D., C.D.S., X.L., T.G.G., L.I.S., Z.V.W.), University of Texas Southwestern Medical Center, Dallas.

4. Advanced Imaging Research Center (G.S., C.R.M.), University of Texas Southwestern Medical Center, Dallas.

5. Touchstone Diabetes Center, Department of Internal Medicine (Y.A.A., S.Z., Y.D., P.E.S.), University of Texas Southwestern Medical Center, Dallas.

6. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (J.Liu, J.W.L.).

7. Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston (L.T., P.L.L.).

8. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (S-J.L.).

9. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge (S.M.D., M.G.V.H.).

10. Department of Internal Medicine (C.R.M.), University of Texas Southwestern Medical Center, Dallas.

11. Department of Radiology (C.R.M.), University of Texas Southwestern Medical Center, Dallas.

12. Dana-Farber Cancer Institute, Boston, MA (M.G.V.H.).

Abstract

Background: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload. Methods: Cardiac-specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac-specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction. Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and nuclear magnetic resonance spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload. Results: We found that PKM1 expression is reduced in failing human and mouse hearts. It is important to note that cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against transverse aortic constriction–induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels. Conclusions: These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.054885

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