Epigenetics in Heart Failure
Abstract
1. Introduction
2. Pathophysiology of Heart Failure
3. DNA Methylation in Heart Failure
4. Histone Modification in Heart Failure
4.1. Histone Methylation
4.2. Histone Acetylation
4.3. BET-Family Bromodomain Proteins
4.4. Histone Phosphorylation, Ubiquitination and Sumoylation
5. Future Directions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Type of Epigenetic Modifications | Examples | Proposed Effects on Heart Failure | References |
---|---|---|---|
DNA hypomethylation | Hypomethylation of MMP2, CTGF increases their expression | Increased collagen turnover and fibrosis in heart failure | [6] |
Hypomethylation of Itga9 and natriuretic peptide A | Cardiac hypertrophy | [7] | |
DNA hypermethylation | Hypermethylation of TIMP4 leads to upregulation of MMP9, a regulator of cardiac remodelling process | Increased cardiac remodelling and heart failure | [8] |
Histone methylation | Reduced H3K4 and H3K9 trimethylation, possibly linked to increased JMJD1C (a histone demethylase) | Non-ischemic dilated cardiomyopathy Increased cardiac hypertrophy and fibrosis induced by angiotensin II Increased atrial natriuretic peptic and brain natriuretic peptide expression | [9] |
Histone acetylation | Acetylation of H3 and H4 by p300 (a HAT) | Phenylephrine-induced hypertrophy and deterioration of systolic function | [10] |
Class II HDAC inhibit HAT, e.g., HDAC5 and HDAC9 | Reduce cardiac hypertrophy with age and in response to constitutive calcineurin activation or pressure overload | [11,12] | |
HDAC4 deletion | Reduced heart failure, with reduced exercise capacity and increased cardiac fatigue | [13] | |
Reduced HDAC6 | Increased myofibril stiffness | [14] | |
HDAC2 (Class I HDAC) | Promotes cardiac hypertrophy, downregulates anti-hypertrophy genes e.g., Klf4, Inpp5f, Gsk3b | [15] | |
Decrease in nuclear HDAC1 (Class I HDAC) in cardiac fibroblast leads to increased acetylation of H3K18 and H3K27 | Inhibition of cardiac fibroblast proliferation and fibrosis-associated proteins | [16] | |
Class III HDAC or sirtuins e.g., Sirt1, Sirt2 and Sirt6 deacetylates H3K9 | Decrease oxidative damage, improve mitochondrial function Reduced cardiac hypertrophy, apoptosis and fibrosis, cardiac dysfunction and expression of senescence markers in pressure overload Reduced cardiac lipid accumulation and diastolic dysfunction | [17,18,19] | |
Acetylation of H3K9 on the promotor of hypertrophic response genes | Increased in heart failure induced by high salt diet, increased in hypertrophy stage | [20] | |
BET-family bromodomain proteins interact with acetylated chromatin, e.g., BRD4 | Drives pathologic cardiac remodelling in cardiac stress, inhibition of BRD4 suppressed cardiomyocyte hypertrophy | [21] | |
Histone phosphorylation | H3 serine-10 phosphorylation | Increased in early phases of cardiac hypertrophy with pressure overload | [22,23] |
Histone ubiquitination | Ubiquitination of H2A on lysine 119 by PRC1 associated with gene silencing | Reperfusion injury after myocardial ischemia, uncertain effects in heart failure | [24] |
Histone sumoylation | Overexpression of SUMO1 | Prevent cardiac hypertrophy and heart failure development | [25] |
SUMO2 and SUMO3 overexpression | Cardiomyopathy associated with heart failure | [26] |
Compound | Epigenetic Target | Animal Model/Clinical Trial | Cardiac Effect | References |
---|---|---|---|---|
5-azcytidine | DNA methyltransferase inhibition | Hypertension-induced hypertrophy in rat | Reduced hypertrophy and fibrosis | [34] |
5′-Aza-2′-deoxycytidine | DNA methyltransferase inhibition | Norepinephrine-induced hypertrophy in rat Spontaneously hypertensive rat | Reduced hypertrophy | [61,62] |
RG108 | DNA methyltransferase | TAC model in rat | Reduced hypertrophy | [63] |
Curcumin | P300 histone acetyltransferase inhibitor | Phenylephrine-induced hypertrophy in rat Dahl salt-sensitive rat | Reduced hypertrophy and systolic dysfunction | [10] |
TSA | Class I and II HDAC inhibitor | TAC model in mice Hop transgenic mice | Reduced hypertrophy and fibrosis | [42,64] |
Scriptaid | Class I and II HDAC inhibitor | TAC model in mice | Reduced hypertrophy and fibrosis | [42] |
Givinsostat (ITF2357) | Class I and II HDAC inhibitor | Uninephrectomy and DOCA-salt hypertensive mouse model, Dahl salt-sensitive rat | Reduced hypertrophy and fibrosis | [65,66] |
Valproic acid | Class I HDAC inhibitor | TAC model in mice Hop transgenic mice Angiotensin II-induced hypertrophy in mice | Reduced hypertrophy | [67,68,69] |
API-D | Class I HDACs | TAC model in mice | Reduced hypertrophy and fibrosis | [43] |
Apabetalone | BRD4 inhibitor | Phase 3 clinical trial | Reduced heart failure hospitalizations | [45] |
JQ1 | BET proteins | TAC model in mice Phenylephrine-induced hypertrophy in mice | Reduced hypertrophy and fibrosis | [21] |
JIB-04 | Jumonji family (H3K9 demethylase) inhibitor | TAC model in mice | Reduced hypertrophy and fibrosis | [70] |
Chaetocin | H3K9 methyltransferase inhibitor | Dahl salt-sensitive rat | Reduced hypertrophy | [41] |
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Ho, J.S.Y.; Jou, E.; Khong, P.-L.; Foo, R.S.Y.; Sia, C.-H. Epigenetics in Heart Failure. Int. J. Mol. Sci. 2024, 25, 12010. https://doi.org/10.3390/ijms252212010
Ho JSY, Jou E, Khong P-L, Foo RSY, Sia C-H. Epigenetics in Heart Failure. International Journal of Molecular Sciences. 2024; 25(22):12010. https://doi.org/10.3390/ijms252212010
Chicago/Turabian StyleHo, Jamie Sin Ying, Eric Jou, Pek-Lan Khong, Roger S. Y. Foo, and Ching-Hui Sia. 2024. "Epigenetics in Heart Failure" International Journal of Molecular Sciences 25, no. 22: 12010. https://doi.org/10.3390/ijms252212010
APA StyleHo, J. S. Y., Jou, E., Khong, P.-L., Foo, R. S. Y., & Sia, C.-H. (2024). Epigenetics in Heart Failure. International Journal of Molecular Sciences, 25(22), 12010. https://doi.org/10.3390/ijms252212010