Histone H3 Lysine 18 Lactylation Promotes Cardiac Hypertrophy Through Activating GATA Binding Protein 4 Signaling

TL;DR

This study shows that histone H3 lysine 18 lactylation promotes heart enlargement by activating GATA4, offering new insights into heart disease mechanisms.

Contribution

The study identifies H3K18la as a novel epigenetic mechanism driving cardiac hypertrophy through GATA4 activation.

Findings

Elevated H3K18la levels correlate with cardiac hypertrophy in mice and human patients.

Inhibition of lactylation reverses hypertrophic effects, confirming its direct role.

H3K18la enhances GATA4 transcriptional activity, which is essential for hypertrophic gene expression.

Abstract

Histone lactylation, particularly histone H3 lysine 18 lactylation (H3K18la), modulates gene expression profile in diverse cellular processes, which has emerged as a critical factor in cardiovascular disease pathogenesis. However, its specific role in cardiac hypertrophy remains unclear. This study investigates the mechanism of H3K18la in promoting cardiac hypertrophy using transverse aortic constriction‐induced mice model and a phenylephrine‐induced hypertrophic cardiomyocyte model. We found that elevated levels of Pan‐Kla and H3K18la were detected in hypertrophic left ventricular tissues and cardiomyocytes, accompanied by increased heart and left ventricle weights, enlarged cardiomyocyte cross‐sectional areas and heightened expression of ANP, BNP, and β‐MHC. Clinical observations revealed a positive correlation between serum lactate levels and hypertrophic cardiomyopathy in patients. Furthermore, inhibition of lactylation reversed these effects, suggesting a direct role of H3K18la in hypertrophic gene expression. Mechanistically, H3K18la was found to interact with GATA4, enhancing its transcriptional activity as demonstrated by increased ANP promoter activity. Moreover, suppression of GATA4 mitigated the hypertrophic response, highlighting its crucial role downstream of H3K18la. Our findings identify H3K18la lactylation as a novel epigenetic mechanism driving cardiac hypertrophy through GATA4 activation. This implicates potential therapeutic targets for hypertrophic heart diseases.

Proposed model of the interaction of the H3K18la lactylation with GATA4 to promote the cardiac hypertrophy. The image was created using Home for Researchers.com.

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