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

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.

Keywords

cardiac hypertrophy / histone lactylation / hypertension / transcription factor

References

[1] Y. Bai, X. Zhang, Y. Li, et al., “Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy, ” Circulation Research 134, no. 4 (2024): 393-410.

[2] X. Chen, X. Li, X. Wu, et al., “Integrin Beta-Like 1 Mediates Fibroblast-cardiomyocyte Crosstalk to Promote Cardiac Fibrosis and Hypertrophy, ” Cardiovascular Research 119, no. 10 (2023): 1928-1941.

[3] J. Y. Kang, D. Mun, Y. Chun, et al., “Engineered Small Extracellular Vesicle-mediated NOX4 siRNA Delivery for Targeted Therapy of Cardiac Hypertrophy, ” Journal of Extracellular Vesicles 12, no. 10 (2023): e12371.

[4] J. Ritterhoff and R. Tian, “Metabolic Mechanisms in Physiological and Pathological Cardiac Hypertrophy: New Paradigms and Challenges, ” Nature Reviews Cardiology 20, no. 12 (2023): 812-829.

[5] J. Shi, C. Yang, J. Zhang, et al., “NAT10 Is Involved in Cardiac Remodeling through ac4C-Mediated Transcriptomic Regulation, ” Circulation Research 133, no. 12 (2023): 989-1002.

[6] P. J. Stanczyk, Y. Tatekoshi, J. S. Shapiro, et al., “DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK through Actin Depolymerization, ” Circulation 148, no. 20 (2023): 1582-1592.

[7] J. Wan, Z. Zhang, C. Wu, et al., “Astragaloside IV Derivative HHQ16 Ameliorates Infarction-induced Hypertrophy and Heart Failure Through Degradation of lncRNA4012/9456, ” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 414.

[8] X. Wei, J. Jin, and J. Wu, “Cardiac-specific BACH1 Ablation Attenuates Pathological Cardiac Hypertrophy by Inhibiting the Ang II Type 1 Receptor Expression and the Ca2+/CaMKII Pathway, ” Cardiovascular Research 119, no. 9 (2023): 1842-1855.

[9] X. Yang, H. C. Chang, Y. Tatekoshi, et al., “SIRT2 inhibition Protects Against Cardiac Hypertrophy and Ischemic Injury, ” Elife 12 (2023): e85571.

[10] H. Fan, F. Yang, Z. Xiao, et al., “Lactylation: Novel Epigenetic Regulatory and Therapeutic Opportunities,” American Journal of Physiology Endocrinology and Metabolism 324, no. 4 (2023): E330-E338.

[11] D. Li, L. Zhang, Q. Gong, et al., “The Role of Myocardial Energy Metabolism Perturbations in Diabetic Cardiomyopathy: From the Perspective of Novel Protein Post-translational Modifications, ” Clin Epigenetics 17, no. 1 (2025): 15.

[12] X. Li, P. Cai, X. Tang, Y. Wu, Y. Zhang, and X. Rong, “Lactylation Modification in Cardiometabolic Disorders: Function and Mechanism, ” Metabolites 14, no. 4 (2024): 217.

[13] J. Ouyang, H. Wang, and J. Huang, “The Role of Lactate in Cardiovascular Diseases, ” Cell Communication and Signaling 21, no. 1 (2023): 317.

[14] J. Wang, Z. Wang, Q. Wang, X. Li, and Y. Guo, “Ubiquitous Protein Lactylation in Health and Diseases, ” Cellular & Molecular Biology Letters 29, no. 1 (2024): 23.

[15] H. Zhang, J. Zhao, J. Yu, et al., “Lactate Metabolism and Lactylation in Cardiovascular Disease: Novel Mechanisms and Therapeutic Targets, ” Frontiers in Cardiovascular Medicine 11 (2024): 1489438.

[16] M. Fan, K. Yang, X. Wang, et al., “Lactate Promotes Endothelial-to-mesenchymal Transition via Snail1 Lactylation After Myocardial Infarction, ” Science Advances 9, no. 5 (2023): eadc9465.

[17] W. Zhu, S. Guo, J. Sun, Y. Zhao, and C. Liu, “Lactate and Lactylation in Cardiovascular Diseases: Current Progress and Future Perspectives, ” Metabolism 158 (2024): 155957.

[18] E. Galle, C. W. Wong, A. Ghosh, et al., “H3K18 lactylation Marks Tissue-specific Active Enhancers, ” Genome Biology 23, no. 1 (2022): 207.

[19] A. A. Cluntun, R. Badolia, S. Lettlova, et al., “The Pyruvate-lactate Axis Modulates Cardiac Hypertrophy and Heart Failure, ” Cell Metabolism 33, no. 3 (2021): 629-648. e10.

[20] P. Chen, Z. Guo, C. Chen, et al., “Identification of Dual Histone Modification-binding Protein Interaction by Combining Mass Spectrometry and Isothermal Titration Calorimetric Analysis, ” Journal of Advanced Research 22 (2020): 35-46.

[21] D. Wu, C. B. Spencer, L. Ortoga, H. Zhang, and C. Miao, “Histone Lactylation-regulated METTL3 Promotes Ferroptosis via m6A-modification on ACSL4 in Sepsis-associated Lung Injury, ” Redox Biology 74 (2024): 103194.

[22] J. Wu, M. Hu, H. Jiang, et al., “Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis, ” Advanced Science (Weinheim) 10, no. 31 (2023): e2301300.

[23] J. Qiao, Y. Tan, H. Liu, et al., “Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury, ” Advanced Science (Weinheim) 11, no. 28 (2024): e2307216.

[24] P. Wang, D. Xie, T. Xiao, et al., “H3K18 lactylation Promotes the Progression of Arsenite-related Idiopathic Pulmonary Fibrosis via YTHDF1/m6A/NREP, ” Journal of Hazardous Materials 461 (2024): 132582.

[25] L. Wei, X. Yang, J. Wang, et al., “H3K18 lactylation of Senescent Microglia Potentiates Brain Aging and Alzheimer's Disease Through the NFkappaB Signaling Pathway, ” Journal of Neuroinflammation 20, no. 1 (2023): 208.

[26] H. Xie, J. Li, N. Lian, et al., “Defective Branched-chain Amino Acid Catabolism in Dorsal Root Ganglia Contributes to Mechanical Pain, ” Embo Reports 24, no. 11 (2023): e56958.

[27] Y. Yu, X. Huang, C. Liang, and P. Zhang, “Evodiamine Impairs HIF1A Histone Lactylation to Inhibit Sema3A-mediated Angiogenesis and PD-L1 by Inducing Ferroptosis in Prostate Cancer, ” European Journal of Pharmacology 957 (2023): 176007.

[28] J. Zhou, W. Xu, Y. Wu, et al., “GPR37 promotes Colorectal Cancer Liver Metastases by Enhancing the Glycolysis and Histone Lactylation via Hippo Pathway, ” Oncogene 42, no. 45 (2023): 3319-3330.

[29] B. Chen, Y. Deng, Y. Hong, et al., “Metabolic Recoding of NSUN2-Mediated M(5)C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m(5)C-ENO1 Positive Feedback Loop, ” Advanced Science (Weinheim) 11, no. 28 (2024): e2309840.

[30] W. Ma, K. Jia, H. Cheng, et al., “Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation, ” Circulation Research 134, no. 11 (2024): 1427-1447.

[31] M. Dong, Y. Zhang, M. Chen, et al., “ASF1A-dependent P300-mediated Histone H3 Lysine 18 Lactylation Promotes Atherosclerosis by Regulating EndMT, ” Acta Pharmaceutica Sinica B 14, no. 7 (2024): 3027-3048.

[32] T. Desgeorges, E. Galle, J. Zhang, F. von Meyenn, and K. De Bock, “Histone Lactylation in Macrophages Is Predictive for Gene Expression Changes During Ischemia Induced-muscle Regeneration, ” Molecular Metabolism 83 (2024): 101923.

[33] M. J. Valimaki and H. J. Ruskoaho, “Targeting GATA4 for Cardiac Repair, ” Iubmb Life 72, no. 1 (2020): 68-79.

[34] R. S. Patel, R. Romero, E. V. Watson, et al., “A GATA4-regulated Secretory Program Suppresses Tumors Through Recruitment of Cytotoxic CD8 T Cells, ” Nature Communications 13, no. 1 (2022): 256.

[35] Z. L. Robbe, W. Shi, L. K. Wasson, et al., “CHD4 is Recruited by GATA4 and NKX2-5 to Repress Noncardiac Gene Programs in the Developing Heart, ” Genes & Development 36, no. 7-8 (2022): 468-482.

[36] S. Shimizu, Y. Sunagawa, N. Hajika, et al., “Multimerization of the GATA4 Transcription Factor Regulates Transcriptional Activity and Cardiomyocyte Hypertrophic Response, ” International Journal of Biological Sciences 18, no. 3 (2022): 1079-1095.

[37] Y. Tang, S. Aryal, X. Geng, et al., “TBX20 Improves Contractility and Mitochondrial Function during Direct Human Cardiac Reprogramming, ” Circulation 146, no. 20 (2022): 1518-1536.

[38] P. Zhou, Y. Zhang, I. Sethi, et al., “GATA4 Regulates Developing Endocardium through Interaction with ETS1, ” Circulation Research 131, no. 11 (2022): e152-e168.

[39] X. Lin, Y. Lei, M. Pan, et al., “Augmentation of Scleral Glycolysis Promotes Myopia Through Histone Lactylation, ” Cell Metabolism 36, no. 3 (2024): 511-525. e7.

[40] W. Ma, S. Ao, J. Zhou, et al., “Methylsulfonylmethane Protects Against Lethal Dose MRSA-induced Sepsis Through Promoting M2 Macrophage Polarization, ” Molecular Immunology 146 (2022): 69-77.

[41] Y. Zhao, J. Jiang, P. Zhou, et al., “H3K18 lactylation-mediated VCAM1 Expression Promotes Gastric Cancer Progression and Metastasis via AKT-mTOR-CXCL1 Axis, ” Biochemical Pharmacology 222 (2024): 116120.

[42] N. Wang, W. Wang, and X. Wang, “Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction, ” Circulation Research 131, no. 11 (2022): 893-908.

[43] H. Li, J. D. Xu, X. H. Fang, et al., “Circular RNA circRNA_000203 Aggravates Cardiac Hypertrophy via Suppressing miR-26b-5p and miR-140-3p Binding to Gata4, ” Cardiovascular Research 116, no. 7 (2020): 1323-1334.

[44] J. Wu, H. Zhao, Y. Tao, et al., “Improved Factor Combination for in Vivo Reprogramming of Cardiac Myofibroblast to Cardiomyocyte-Like Cell with Dual Recombinase Tracing, ” Circulation 148, no. 21 (2023): 1728-1731.

[45] W. Yu, X. Huang, X. Tian, et al., “GATA4 regulates Fgf16 to Promote Heart Repair After Injury, ” Development (Cambridge, England) 143, no. 6 (2016): 936-949.

[46] A. He, F. Gu, Y. Hu, et al., “Dynamic GATA4 Enhancers Shape the Chromatin Landscape central to Heart Development and Disease, ” Nature Communications 5 (2014): 4907.

[47] N. Zhang, Y. Zhang, J. Xu, et al., “α-myosin Heavy Chain Lactylation Maintains Sarcomeric Structure and Function and Alleviates the Development of Heart Failure, ” Cell Research 33, no. 9 (2023): 679-698.

[48] W. W. Wang, S. Y. Ji, W. Zhang, et al., “Structure-based Design of Non-hypertrophic Apelin Receptor Modulator, ” Cell 187, no. 6 (2024): 1460-1475. e20.

[49] L. Zhang, H. Han, A. Xu, et al., “Lysozyme 1 Inflamed CCR2(+) Macrophages Promote Obesity-Induced Cardiac Dysfunction, ” Circulation Research 135, no. 5 (2024): 596-613.

[50] S. Yu, Z. Sun, T. Ju, et al., “The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4, ” Advanced Science (Weinheim) 11, no. 29 (2024): e2308769.

[51] X. Li, F. Wu, S. Günther, et al., “Inhibition of Fatty Acid Oxidation Enables Heart Regeneration in Adult Mice, ” Nature 622, no. 7983 (2023): 619-626.

[52] Y. Tang, M. Feng, Y. Su, et al., “Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective against Dilated Cardiomyopathy, ” Circulation 147, no. 22 (2023): 1684-1704.

[53] Q. Liang, S. Wang, X. Zhou, et al., “Essential Role of MESP1-RING1A Complex in Cardiac Differentiation, ” Developmental Cell 57, no. 22 (2022): 2533-2549. e7.

[54] Q. Liang, L. J. De Windt, S. A. Witt, T. R. Kimball, B. E. Markham, and J. D. Molkentin, “The Transcription Factors GATA4 and GATA6 Regulate Cardiomyocyte Hypertrophy in Vitro and in Vivo, ” Journal of Biological Chemistry 276, no. 32 (2001): 30245-30253.

[55] S. Sharma, S. Bhattarai, H. Ara, et al., “SOD2 deficiency in Cardiomyocytes Defines Defective Mitochondrial Bioenergetics as a Cause of Lethal Dilated Cardiomyopathy, ” Redox Biology 37 (2020): 101740.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.