Lactate regulates pathological cardiac hypertrophy via histone lactylation modification

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Metabolic Regulation

Background:

• Cardiac hypertrophy and ventricular remodeling are precursors to heart failure.
• Effective therapeutic targets are needed for myocardial hypertrophy.
• Histone lysine lactylation (HKla) is a novel epigenetic modification linking metabolism and gene expression.

Purpose of the Study:

• To investigate the role of HKla in pathological cardiac hypertrophy.
• To determine if HKla modification is a pathogenic factor in cardiac hypertrophy development.

Main Methods:

• Utilized a mouse model of cardiac hypertrophy induced by transverse aortic constriction.
• Examined HKla expression in neonatal mouse cardiomyocytes stimulated with Ang II.
• Investigated the impact of glucose, lactate, and inhibitors (2-DG, oxamate, GNE-140) on HKla and hypertrophy in vitro.

Main Results:

• HKla expression was significantly elevated in cardiomyocytes from hypertrophic models and Ang II-stimulated cells.
• HKla levels were influenced by glucose metabolism and lactate production.
• Exogenous lactate and glucose upregulated HKla and promoted hypertrophy; inhibitors reduced HKla and inhibited hypertrophy.

Conclusions:

• HKla plays a pivotal role in pathological cardiac hypertrophy.
• HKla modification is influenced by cellular metabolic status.
• Targeting HKla offers a potential therapeutic approach for cardiac hypertrophy and heart failure.