Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling

Tong Wei; Yuetong Guo; Chenglin Huang; Mengwei Sun; Bin Zhou; Jing Gao; Weili Shen

doi:10.1186/s13578-023-01098-0

Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling

Cell Biosci. 2023 Aug 15;13(1):151. doi: 10.1186/s13578-023-01098-0.

Authors

Tong Wei^#^{1

2}, Yuetong Guo^#¹, Chenglin Huang¹, Mengwei Sun³, Bin Zhou⁴, Jing Gao¹, Weili Shen⁵

Affiliations

¹ Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
² Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
³ Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai, 200030, China.
⁴ New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
⁵ Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. weili_shen@hotmail.com.

^# Contributed equally.

Abstract

Background: Cardiac fibroblasts (CFs) and cardiomyocytes are the major cell populations in the heart. CFs not only support cardiomyocytes by producing extracellular matrix (ECM) but also assimilate myocardial nutrient metabolism. Recent studies suggest that the classical intercellular lactate shuttle may function in the heart, with lactate transported from CFs to cardiomyocytes. However, the underlying mechanisms regarding the generation and delivery of lactate from CFs to cardiomyocytes have yet to be explored.

Results: In this study, we found that angiotensin II (Ang II) induced CFs differentiation into myofibroblasts that, driven by cell metabolism, then underwent a shift from oxidative phosphorylation to aerobic glycolysis. During this metabolic conversion, the expression of amino acid synthesis 5-like 1 (GCN5L1) was upregulated and bound to and acetylated mitochondrial pyruvate carrier 2 (MPC2) at lysine residue 19. Hyperacetylation of MPC2^k19 disrupted mitochondrial pyruvate uptake and mitochondrial respiration. GCN5L1 ablation downregulated MPC2^K19 acetylation, stimulated mitochondrial pyruvate metabolism, and inhibited glycolysis and lactate accumulation. In addition, myofibroblast-specific GCN5L1-knockout mice (GCN5L1^fl/fl: Periostin-Cre) showed reduced myocardial hypertrophy and collagen content in the myocardium. Moreover, cardiomyocyte-specific monocarboxylate transporter 1 (MCT1)-knockout mice (MCT1^fl/fl: Myh6-Cre) exhibited blocked shuttling of lactate from CFs to cardiomyocytes and attenuated Ang II-induced cardiac hypertrophy.

Conclusions: Our findings suggest that GCN5L1-MPC2 signalling pathway alters metabolic patterns, and blocking MCT1 interrupts the fibroblast-to-cardiomyocyte lactate shuttle, which may attenuate cardiac remodelling in hypertension.

Keywords: GCN5L1; Lactate shuttle; MCT1; MPC2; Metabolism shift.

Abstract

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