Department of Cardiac Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Institute of Translational Medicine, Shanghai University, Shanghai, China.
J Cell Mol Med. 2024 Aug;28(16):e70022. doi: 10.1111/jcmm.70022.
Under the long-term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post-translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2-DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE-140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition.
在长期的压力过载刺激下，心脏经历胚胎基因激活，导致心肌肥厚和心室重构，最终可发展为心力衰竭。确定有效的治疗靶点对于心肌肥厚的预防和治疗至关重要。组蛋白赖氨酸乳酸化（HKla）是一种新的翻译后修饰，它将细胞代谢与表观遗传调控联系起来。然而，HKla 在病理性心肌肥厚中的具体作用尚不清楚。我们的研究旨在探讨 HKla 修饰是否在心肌肥厚的发展中起致病作用。结果表明，在由主动脉缩窄手术诱导的心肌肥厚动物模型和 Ang II 刺激的新生小鼠心肌细胞中，HKla 表达显著。此外，研究表明 HKla 受葡萄糖代谢和乳酸生成的影响，对各种环境刺激表现出显著的表型变异性。体外实验表明，外源性乳酸和葡萄糖可以上调 HKla 的表达并促进心肌肥厚。相反，使用糖酵解抑制剂（2-DG）、LDH 抑制剂（oxamate）和 LDHA 抑制剂（GNE-140）抑制乳酸生成可降低 HKla 水平并抑制心肌肥厚的发展。综上所述，这些发现确立了 H3K18la 在病理性心肌肥厚中的关键作用，为该疾病的治疗提供了一个新的靶点。
