Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress.
Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress.
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DOI：
10.1016/j.celrep.2020.108087
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发表时间：
2020-09-01
期刊：
影响因子：
8.8
通讯作者：
Wang ZV
中科院分区：
文献类型：
--
作者：
Dai C;Li Q;May HI;Li C;Zhang G;Sharma G;Sherry AD;Malloy CR;Khemtong C;Zhang Y;Deng Y;Gillette TG;Xu J;Scadden DT;Wang ZV
心脏对高血压的反应表现为肥大的生长，在持续的应激下可能会失代偿并进展为心力衰竭。代谢重塑是这一过程的早期事件。然而，它的作用仍有待充分描述。在这里，我们表明，乳酸脱氢酶A(LDHA)，一种关键的糖酵解酶，在心脏中升高，以响应血流动力学应激。心肌细胞限制性LDHA缺失会导致心肌肥大生长缺陷和压力超负荷所致的心力衰竭。在体外培养的心肌细胞中，LDHA的沉默抑制了促肥大刺激的细胞生长，而LDHA的过表达足以促进心肌细胞的生长。此外，我们发现乳酸能够挽救LDHA基因敲除后的生长缺陷。在机制上，乳酸稳定NDRG3(N-myc下调基因家族3)并刺激ERK(细胞外信号调节激酶)。我们的结果提示LDHA/NDRG3轴可能在血流动力学应激反应的适应性心肌细胞生长中起关键作用。戴等人。研究发现，在血流动力学应激下，心脏中LDHA显著增加，心肌细胞特异性LDHA缺失会导致严重的心功能障碍，以应对压力超负荷。LDHA可能通过上调NDRG3和激活ERK来调控适应性生长。
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. Dai et al. find that LDHA is significantly increased in the heart under hemodynamic stress, and cardiomyocyte-specific deletion of LDHA leads to severe cardiac dysfunction in response to pressure overload. LDHA may govern adaptive growth through elevation of NDRG3 and activation of ERK.
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