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

Abstract

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. 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 <i>Ldha</i> 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). 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 lactylation exacerbated pathological remodeling. In vitro, inhibition of lactylation suppressed phenylephrine-induced cardiomyocyte hypertrophy. P300 and GCN5 (general control non-derepressible 5) were identified as candidate lactylation transferases. Cleavage Under Targets and Tagmentation revealed lactate-dependent enrichment of H3K18la (histone H3 lysine 18 lactylation) at the TGFB2 promoter, correlating with increased TGFB2 expression. Cardiac-specific <i>Tgfb2</i> knockdown reversed the prohypertrophic effects of histone lactylation in vivo, while <i>Tgfb2</i> overexpression promoted cardiomyocyte hypertrophy via PI3K/AKT/mTOR (mechanistic target of rapamycin) signaling. Pharmacological inhibition of PI3K or AKT attenuated this effect. Histone lactylation promotes pathological cardiac hypertrophy and heart failure by upregulating TGFB2 and activating PI3K/AKT/mTOR signaling. These findings identify histone lactylation as an epigenetic link between metabolic reprogramming and hypertrophic signaling, and suggest it as a potential therapeutic target for pathological cardiac remodeling.