The pathogenesis of heart failure involves a highly intricate process regulated by diverse epigenetic factors, transcription factors, noncoding RNAs, and cyclins. Notably, the reexpression of embryonic cardiac transcription factors, including GATA, MEF2, and Nkx2.5, is considered to exert critical influence in the initiation and advancement of heart failure. Nevertheless, the precise mechanisms through which epigenetic modifications drive this reprogramming of gene expression remain poorly defined. This investigation aims to clarify the role of histone acetylation in regulating the reexpression of embryonic cardiac transcription factors during heart failure. Our research indicates that during heart failure of mice, there are distinct histone acetylation modifications associated with the reexpression of these factors. Notably, GATA4 and MEF2C show significant increases, whereas Nkx2.5 shows a decrease compared to normal groups during heart failure progression. These findings imply that embryonic GATA4 and MEF2C may promote the development of heart failure, whereas Nkx2.5 does not appear to participate in disease progression. Furthermore, treatment with curcumin, a known inhibitor of histone acetylation, reduces acetylation levels at H3K4, H3K9, and H3K27 within the promoter regions of GATA4 and MEF2C in a murine model of heart failure, leading to downregulation of these genes and subsequent enhancement of cardiac performance. In summary, our study demonstrates that p300 exerts site-specific regulatory effects on various transcription factors via histone modifications, and low acetylation status at specific sites can inhibit reactivation of GATA4 and MEF2C during the myocardial dysfunction period thereby improving cardiac performance of mice.
| [1] |
D. Tomasoni, M. Adamo, C. M. Lombardi, and M. Metra, “Highlights in Heart Failure,” ESC Heart Failure 6, no. 6 (2019): 1105–1127.
|
| [2] |
P. A. Heidenreich, B. Bozkurt, D. Aguilar, et al., “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines,” Circulation 145, no. 18 (2022): e895–e1032.
|
| [3] |
T. A. McDonagh, M. Metra, M. Adamo, et al., “2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure,” European Heart Journal 42, no. 36 (2021): 3599–3726.
|
| [4] |
P. A. Heidenreich, B. Bozkurt, D. Aguilar, et al., “Correction to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines,” Circulation 145, no. 18 (2022): e1033, https://doi.org/10.1161/CIR.0000000000001073.
|
| [5] |
P. A. Heidenreich, B. Bozkurt, D. Aguilar, et al., “Correction to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines,” Circulation 146, no. 13 (2022): e185, https://doi.org/10.1161/CIR.0000000000001097.
|
| [6] |
P. A. Heidenreich, B. Bozkurt, D. Aguilar, et al., “Correction to: 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines,” Circulation 147, no. 14 (2023): e674, https://doi.org/10.1161/CIR.0000000000001142.
|
| [7] |
B. Ziaeian and G. C. Fonarow, “Epidemiology and Aetiology of Heart Failure,” Nature Reviews Cardiology 13, no. 6 (2016): 368–378.
|
| [8] |
E. M. DeFilippis, L. Sinnenberg, N. Reza, et al., “Trends in US Heart Transplant Waitlist Activity and Volume During the Coronavirus Disease 2019 (COVID-19) Pandemic,” JAMA Cardiology 5, no. 9 (2020): 1048–1052.
|
| [9] |
K. Al-Hasani, P. Mathiyalagan, and A. El-Osta, “Epigenetics, Cardiovascular Disease, and Cellular Reprogramming,” Journal of Molecular and Cellular Cardiology 128 (2019): 129–133.
|
| [10] |
M. A. Lorenzana-Carrillo, K. Gopal, N. J. Byrne, et al., “TRIM35-Mediated Degradation of Nuclear PKM2 Destabilizes GATA4/6 and Induces P53 in Cardiomyocytes to Promote Heart Failure,” Science Translational Medicine 14, no. 669 (2022): eabm3565.
|
| [11] |
V. Sharma, S. K. Dash, A. Manhas, J. Radhakrishnan, K. Jagavelu, and R. S. Verma, “Injectable Hydrogel for Co-Delivery of 5-Azacytidine in Zein Protein Nanoparticles With Stem Cells for Cardiac Function Restoration,” International Journal of Pharmaceutics 603 (2021): 120673.
|
| [12] |
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.
|
| [13] |
S. C. Materna, T. Sinha, R. M. Barnes, K. Lammerts van Bueren, and B. L. Black, “Cardiovascular Development and Survival Require Mef2c Function in the Myocardial but Not the Endothelial Lineage,” Developmental Biology 445, no. 2 (2019): 170–177.
|
| [14] |
J.-H. Hong and H.-G. Zhang, “Transcription Factors Involved in the Development and Prognosis of Cardiac Remodeling,” Frontiers in Pharmacology 13 (2022): 828549.
|
| [15] |
S. Wang, Y. Li, Y. Xu, et al., “AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome,” Circulation Research 126, no. 8 (2020): 1024–1039.
|
| [16] |
H. Sun, J. Zhu, T. Lu, X. Huang, and J. Tian, “Curcumin-Mediated Cardiac Defects in Mouse Is Associated With a Reduced Histone H3 Acetylation and Reduced Expression of Cardiac Transcription Factors,” Cardiovascular Toxicology 14, no. 2 (2014): 162–169.
|
| [17] |
W. Zhou, D. Jiang, J. Tian, et al., “Acetylation of H3K4, H3K9, and H3K27 Mediated by P300 Regulates the Expression of GATA4 in Cardiocytes,” Genes & Diseases 6, no. 3 (2019): 318–325.
|
| [18] |
R. Chakraborty, A. C. Ostriker, Y. Xie, et al., “Histone Acetyltransferases P300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity,” Circulation 145, no. 23 (2022): 1720–1737.
|
| [19] |
A. K. Ghosh, “P300 in Cardiac Development and Accelerated Cardiac Aging,” Aging and Disease 11, no. 4 (2020): 916–926.
|
| [20] |
P. Zhou, N. J. VanDusen, Y. Zhang, et al., “Dynamic Changes in P300 Enhancers and Enhancer-Promoter Contacts Control Mouse Cardiomyocyte Maturation,” Developmental Cell 58, no. 10 (2023): 898–914.e7.
|
| [21] |
W. Song, X. Zhang, S. He, et al., “68Ga-FAPI PET Visualize Heart Failure: From Mechanism to Clinic,” European Journal of Nuclear Medicine and Molecular Imaging 50, no. 2 (2023): 475–485.
|
| [22] |
M. Nakamura and J. Sadoshima, “Mechanisms of Physiological and Pathological Cardiac Hypertrophy,” Nature Reviews Cardiology 15, no. 7 (2018): 387–407.
|
| [23] |
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.
|
| [24] |
H. Tani, T. Sadahiro, Y. Yamada, et al., “Direct Reprogramming Improves Cardiac Function and Reverses Fibrosis in Chronic Myocardial Infarction,” Circulation 147, no. 3 (2023): 223–238.
|
| [25] |
R. S. Leigh, H. J. Ruskoaho, and B. L. Kaynak, “Cholecystokinin Peptide Signaling Is Regulated by a TBX5-MEF2 Axis in the Heart,” Peptides 136 (2021): 170459.
|
| [26] |
J.-A. Kim, M. Kwon, and J. Kim, “Allosteric Regulation of Chromatin-Modifying Enzymes,” Biochemistry 58, no. 1 (2019): 15–23.
|
| [27] |
N. Gilbert, “Biophysical Regulation of Local Chromatin Structure,” Current Opinion in Genetics & Development 55 (2019): 66–75.
|
| [28] |
A. A. Reyes, R. D. Marcum, and Y. He, “Structure and Function of Chromatin Remodelers,” Journal of Molecular Biology 433, no. 14 (2021): 166929.
|
| [29] |
Y. Han, J. Nie, D.-W. Wang, and L. Ni, “Mechanism of Histone Deacetylases in Cardiac Hypertrophy and Its Therapeutic Inhibitors,” Frontiers in Cardiovascular Medicine 9 (2022): 931475.
|
| [30] |
B. Gonzalez-Teran, M. Pittman, F. Felix, et al., “Transcription Factor Protein Interactomes Reveal Genetic Determinants in Heart Disease,” Cell 185, no. 5 (2022): 794–814.e30.
|
| [31] |
G. A. Garry, R. Bassel-Duby, and E. N. Olson, “Direct Reprogramming as a Route to Cardiac Repair,” Seminars in Cell & Developmental Biology 122 (2022): 3–13.
|
| [32] |
A. H. M. Pereira, A. C. Cardoso, S. R. Consonni, et al., “MEF2C Repressor Variant Deregulation Leads to Cell Cycle Re-Entry and Development of Heart Failure,” EBioMedicine 51 (2020): 102571.
|
| [33] |
C. Liu, L. Zhang, W. Cui, et al., “Erratum Regarding Previously Published Research Papers,” EBioMedicine 66 (April 2021): 103295, https://doi.org/10.1016/j.ebiom.2021.103295.
|
| [34] |
E. G. Behiry, M. A. Al-Azzouny, D. Sabry, O. G. Behairy, and N. E. Salem, “Association of NKX2-5, GATA4, and TBX5 Polymorphisms With Congenital Heart Disease in Egyptian Children,” Molecular Genetics & Genomic Medicine 7, no. 5 (2019): e612.
|
| [35] |
R. M. W. Colpaert and M. Calore, “Epigenetics and microRNAs in Cardiovascular Diseases,” Genomics 113, no. 2 (2021): 540–551.
|
| [36] |
C. Moutinho and M. Esteller, “MicroRNAs and Epigenetics,” in miRNA and Cancer, ed. P. B. Fisher and K. D. Tew (Elsevier, 2017), 189–220, https://doi.org/10.1016/bs.acr.2017.06.003.
|
| [37] |
D. Chen, H. Wang, and X. Cai, “Curcumin Interferes With Sepsis-Induced Cardiomyocyte Apoptosis via TLR1 Inhibition,” Revista Portuguesa de Cardiologia: Orgao oficial da Sociedade Portuguesa de Cardiologia (Portuguese Journal of Cardiology: An Official Journal of the Portuguese Society of Cardiology) 42, no. 3 (2023): 209–221, https://doi.org/10.1016/j.repc.2023.01.013.
|
| [38] |
T. Li, J. Jin, F. Pu, et al., “Cardioprotective Effects of Curcumin Against Myocardial I/R Injury: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies,” Frontiers in Pharmacology 14 (2023): 1111459.
|
| [39] |
W. Zhang, S. Qian, P. Kang, and C. Shi, “Curcumin Attenuates Ferroptosis-Induced Myocardial Injury in Diabetic Cardiomyopathy Through the Nrf2 Pathway,” Cardiovascular Therapeutics 2022, no. 1 (2022): 3159717.
|
| [40] |
Y. Yuan, H. Huang, T. Hu, et al., “Curcumin Pretreatment Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Ferroptosis, Autophagy and Apoptosis via HES1,” International Journal of Molecular Medicine 54, no. 6 (2024): 110.
|
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2026 The Author(s). Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children's Hospital of Chongqing Medical University.
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