Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling.
Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling.
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DOI：
10.1186/s13578-023-01098-0
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发表时间：
2023-08-15
影响因子：
7.5
通讯作者：
Shen, Weili
中科院分区：
文献类型：
--
作者：
Wei, Tong;Guo, Yuetong;Huang, Chenglin;Sun, Mengwei;Zhou, Bin;Gao, Jing;Shen, Weili
心脏成纤维细胞（CF）和心肌细胞是心脏中的主要细胞群。CFs不仅通过产生细胞外基质（ECM）支持心肌细胞，而且还吸收心肌营养代谢。最近的研究表明，经典的细胞间乳酸穿梭可能在心脏中起作用，乳酸从CF运输到心肌细胞。然而，关于乳酸从CF到心肌细胞的产生和递送的潜在机制还有待探索。在这项研究中，我们发现血管紧张素II（Ang II）诱导CFs分化为肌成纤维细胞，由细胞代谢驱动，然后经历了从氧化磷酸化到有氧糖酵解的转变。在这种代谢转化过程中，氨基酸合成5样1（GCN 5L 1）的表达上调，并结合到乙酰化线粒体丙酮酸载体2（MPC 2）的赖氨酸残基19。MPC 2k 19的过度乙酰化破坏线粒体丙酮酸摄取和线粒体呼吸。GCN 5L 1消融下调MPC 2K 19乙酰化，刺激线粒体丙酮酸代谢，并抑制糖酵解和乳酸积累。此外，肌成纤维细胞特异性GCN 5L 1基因敲除小鼠（GCN 5L 1fl/fl：Periostin-Cre）显示心肌肥大和心肌胶原含量降低。此外，心肌细胞特异性单羧酸转运蛋白1（MCT 1）基因敲除小鼠（MCT 1fl/fl：Myh 6-Cre）表现出阻断乳酸从CF到心肌细胞的穿梭，并减弱了Ang II诱导的心肌肥大。我们的研究结果表明，GCN 5L 1-MPC 2信号通路改变代谢模式，阻断MCT 1中断成纤维细胞到心肌细胞的乳酸穿梭，这可能会减弱高血压的心脏重塑。在线版本包含补充材料，可通过10.1186/s13578-023-01098-0获得。1.血管紧张素II增加乳酸的生产过程中CFs分化成肌成纤维细胞。2. GCN 5L 1介导的MPC 2K 19乙酰化降低MPC活性。3. MPC 2K 19的乙酰化改变CF的代谢模式。4.阻断MCT 1活性可破坏乳酸穿梭并减弱心肌细胞肥大。在线版本包含补充材料，可通过10.1186/s13578-023-01098-0获得。
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. 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. 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. The online version contains supplementary material available at 10.1186/s13578-023-01098-0. 1. Ang II elevated lactate production during CFs differentiation into myofibroblasts. 2. GCN5L1-mediated MPC2K19 acetylation reduces MPC activity. 3. Acetylation of MPC2K19 alters CFs metabolic patterns. 4. Blocking MCT1 activity disrupts the lactate shuttle and attenuates cardiomyocyte hypertrophy. The online version contains supplementary material available at 10.1186/s13578-023-01098-0.
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影响因子：
11.1
作者：
Li A;Liu Q;Li Q;Liu B;Yang Y;Zhang N
通讯作者：
Zhang N
影响因子：
20.1
作者：
Kaur, Harmandeep;Takefuji, Mikito;Wettschureck, Nina
通讯作者：
Wettschureck, Nina
影响因子：
4.1
作者：
Karsy, Michael;Guan, Jian;Huang, L. Eric
通讯作者：
Huang, L. Eric
C 端结合蛋白 1 通过黑色素瘤细胞中 MPC1 和 MPC2 的反馈调节来调节细胞氧化还原。
DOI：
10.12659/msm.912735
发表时间：
2018-10-25
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Deng Y;Li H;Yin X;Liu H;Liu J;Guo D;Shi Z
通讯作者：
Shi Z
影响因子：
3.2
作者：
Fu, Ze;Guo, Jiabin;Peng, Shuangqing
通讯作者：
Peng, Shuangqing