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Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling
Tong Wei1,2, Yuetong Guo1, Chenglin Huang1
1Department 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.
Insights
Cardiac fibroblasts shift metabolism to produce lactate, fueling cardiomyocytes. Targeting GCN5L1-MPC2 signaling and the lactate shuttle may reduce cardiac remodeling in hypertension.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Molecular Cardiology
Background:
- Cardiac fibroblasts (CFs) and cardiomyocytes are key heart cells.
- CFs support cardiomyocytes and influence nutrient metabolism.
- Intercellular lactate transport from CFs to cardiomyocytes is suggested but mechanistically unexplored.
Purpose of the Study:
- To investigate the mechanisms of lactate generation and transfer from CFs to cardiomyocytes.
- To explore the role of specific signaling pathways and transporters in cardiac metabolism and remodeling.
Main Methods:
- Angiotensin II (Ang II) treatment to induce CF differentiation into myofibroblasts.
- Analysis of metabolic shifts, including oxidative phosphorylation and aerobic glycolysis.
- Investigated the role of GCN5L1 (an acetyltransferase) and MPC2 (mitochondrial pyruvate carrier).
- Utilized knockout mouse models (myofibroblast-specific GCN5L1 knockout and cardiomyocyte-specific MCT1 knockout).
Main Results:
- Ang II induced CFs to undergo aerobic glycolysis, upregulating GCN5L1, which acetylated MPC2, inhibiting mitochondrial pyruvate uptake and respiration.
- GCN5L1 ablation reversed these metabolic changes, reducing glycolysis and lactate.
- Myofibroblast-specific GCN5L1 knockout reduced cardiac hypertrophy and collagen deposition.
- Cardiomyocyte-specific MCT1 knockout blocked lactate transfer and attenuated Ang II-induced cardiac hypertrophy.
Conclusions:
- The GCN5L1-MPC2 signaling pathway modulates cardiac cell metabolism.
- Blocking the monocarboxylate transporter 1 (MCT1) disrupts the fibroblast-to-cardiomyocyte lactate shuttle.
- Targeting these pathways may offer therapeutic strategies to attenuate cardiac remodeling in hypertension.
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 MPC2k19 disrupted mitochondrial pyruvate uptake and mitochondrial respiration. GCN5L1 ablation downregulated MPC2K19 acetylation, stimulated mitochondrial pyruvate metabolism, and inhibited glycolysis and lactate accumulation. In addition, myofibroblast-specific GCN5L1-knockout mice (GCN5L1fl/fl: Periostin-Cre) showed reduced myocardial hypertrophy and collagen content in the myocardium. Moreover, cardiomyocyte-specific monocarboxylate transporter 1 (MCT1)-knockout mice (MCT1fl/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.
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