Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Chongshan Dai; Qinfeng Li; Herman I May; Chao Li; Guangyu Zhang; Gaurav Sharma; A Dean Sherry; Craig R Malloy; Chalermchai Khemtong; Yuannyu Zhang; Yingfeng Deng; Thomas G Gillette; Jian Xu; David T Scadden; Zhao V Wang

doi:10.1016/j.celrep.2020.108087

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Cell Rep. 2020 Sep 1;32(9):108087. doi: 10.1016/j.celrep.2020.108087.

Authors

Chongshan Dai¹, Qinfeng Li², Herman I May¹, Chao Li¹, Guangyu Zhang¹, Gaurav Sharma³, A Dean Sherry⁴, Craig R Malloy⁵, Chalermchai Khemtong⁶, Yuannyu Zhang⁷, Yingfeng Deng⁸, Thomas G Gillette¹, Jian Xu⁷, David T Scadden⁹, Zhao V Wang¹⁰

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang 310016, China; Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.
³ Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Chemistry, University of Texas in Dallas, Dallas, TX 75080, USA.
⁵ Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02138, USA.
¹⁰ Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: zhao.wang@utsouthwestern.edu.

Abstract

The heart manifests hypertrophic growth in response to high blood pressure, which may decompensate and progress to heart failure under persistent stress. Metabolic remodeling is an early event in this process. However, its role remains to be fully characterized. Here, we show that lactate dehydrogenase A (LDHA), a critical glycolytic enzyme, is elevated in the heart in response to hemodynamic stress. Cardiomyocyte-restricted deletion of LDHA leads to defective cardiac hypertrophic growth and heart failure by pressure overload. Silencing of LDHA in cultured cardiomyocytes suppresses cell growth from pro-hypertrophic stimulation in vitro, while overexpression of LDHA is sufficient to drive cardiomyocyte growth. Furthermore, we find that lactate is capable of rescuing the growth defect from LDHA knockdown. Mechanistically, lactate stabilizes NDRG3 (N-myc downregulated gene family 3) and stimulates ERK (extracellular signal-regulated kinase). Our results together suggest that the LDHA/NDRG3 axis may play a critical role in adaptive cardiomyocyte growth in response to hemodynamic stress.

Keywords: ERK; LDHA; NDRG3; cardiac hypertrophy; heart failure; lactate; pathological cardiac remodeling; pressure overload.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiomegaly / physiopathology*
Cells, Cultured
Heart Failure / physiopathology*
Hemodynamics
Humans
Lactate Dehydrogenase 5 / metabolism*
Signal Transduction

Substances

Lactate Dehydrogenase 5

Abstract

Publication types

MeSH terms

Substances

Grants and funding