Histone Lactylation Promotes Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Regulating TGFB2 Expression

作者：Miao Chen, Zhen Wang, Jing Li, Peng Teng, Yinze Wei, Weidong Li, Yong Cui, Liang Ma, Hongfei Xu · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326185 · 被引用次数：11 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors、Histone Deacetylase Inhibitors Research

BACKGROUND: Cardiac hypertrophy is accompanied by profound metabolic remodeling, including enhanced glycolysis. Histone lactylation, a posttranslational modification linked to glycolytic activity, has been shown to regulate gene transcription. However, its role in cardiac hypertrophy remains unclear. METHODS: Histone lactylation was assessed in failing human and mouse hearts. Male mice subjected to transverse aortic constriction were treated with oxamate (an LDHA [lactate dehydrogenase A] inhibitor) or sodium lactate to modulate histone lactylation. Cardiomyocyte-specific Ldha deletion was also evaluated. In vitro, phenylephrine-stimulated neonatal rat ventricular myocytes were used to examine the effects of lactylation inhibition. Potential histone lactylation transferases were identified by coimmunoprecipitation. Promoter-specific histone lactylation was analyzed by Cleavage Under Targets and Tagmentation and ChIP quantitative polymerase chain reaction, and transcriptional regulation was further evaluated by nascent RNA-seq. TGFB2 (transforming growth factor β2) function was investigated using AAV-shRNA knockdown and lentiviral overexpression in combination with pharmacological inhibition of PI3K (phosphoinositide 3-kinase) or AKT (protein kinase B). RESULTS: Histone lactylation was elevated in failing human and mouse hearts. Reducing lactylation attenuated transverse aortic constriction-induced hypertrophy and fibrosis, preserving cardiac function, whereas increasing lacty...