Jooyeop Lee; Joon Ho Moon

doi:10.4093/dmj.2024.0551

Articles

Page Path: HOME > Diabetes Metab J > Volume 48(6); 2024 > Article

Letter Targeting Cardiac Fibrosis in Diabetic Heart Failure: The Role of the EZH2, AMPK, and PPAR-γ Pathways (Diabetes Metab J 2024;48:716-29): Jooyeop Lee¹, Joon Ho Moon²; Diabetes & Metabolism Journal 2024;48(6):1176-1178.
DOI: https://doi.org/10.4093/dmj.2024.0551
Published online: November 21, 2024

148 Views
11 Download

¹Department of Internal Medicine, Armed Forces Yangju Hospital, Yangju, Korea

²Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

Corresponding author: Joon Ho Moon

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea E-mail: moonjoonho@gmail.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next

Full Article

Download PDF

NOTES
REFERENCES
About this article

See the reply "Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway (Diabetes Metab J 2024;48:716-29)" in Volume 48 on page 1181.

See the article "Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway" on page 716.

Cardiovascular disease remains the leading cause of death globally, and heart failure has emerged as a major complication of type 2 diabetes mellitus [1]. Impaired cardiac metabolic flexibility, cardiac adrenergic signaling, and epicardial adipose tissue affect endothelial cells, vascular smooth muscle cells, cardiomyocytes, and cardiac fibroblasts to contribute to the development of diabetic heart failure [2,3]. Among diabetes medications, sodium glucose co-transporter 2 inhibitors are recognized for their cardioprotective effects in reducing hospitalizations related to heart failure and cardiovascular mortality [4]. Novel treatment for diabetic heart failure with distinct mechanisms of action could provide substantial benefits for the management of diabetic patients.

Li et al. [5] elucidated the mechanism of cardiac fibrosis via the AMP-activated protein kinase (AMPK)/enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)/H3K27me3/peroxisome proliferator-activated receptor γ (PPAR-γ) signaling pathway using rat models and primary cardiac fibroblasts. To achieve this, the authors evaluated the expression of H3K-27me3, EZH2, and myocardial fibrosis proteins in primary cardiac fibroblasts exposed to high glucose, GSK126, A769662, or rosiglitazone. Additionally, diabetic rat and mouse models were established, and left ventricular function was assessed via echocardiography. The study demonstrated that high glucose inhibited AMPK-mediated phosphorylation of EZH2, and that reduced EZH2 phosphorylation inhibited PPAR-γ transcription. A negative correlation between PPAR-γ and myocardial fibrosis was observed. Consistent with this mechanism, the administration of GSK126 (a competitive inhibitor of EZH2), A769662 (a specific AMPK agonist), and rosiglitazone (an agonist for PPAR-γ) resulted in a reduction of cardiac fibrosis. Consequently, this study identifies potential therapeutic targets for diabetic heart failure.

Despite the significant findings, several aspects of this study warrant further examination and discussion. First, if activation of AMPK suppresses EZH2-mediated H3K27me3 and alleviates cardiac fibrosis, it raises the question of whether metformin, a known AMPK activator, might also improve diabetic heart failure. Several studies have reported a beneficial effect of metformin on improving prognosis of diabetic heart failure including mortality and hospitalization [6]. The mechanisms underlying the cardioprotective effects of metformin appear to vary. One investigation indicates that metformin inhibits the transforming growth factor β1 (TGF-β1)-Smad3 signaling pathway to reduce the occurrence of cardiac fibrosis [7]. In comparison, Li et al. [5] showed that AMPK-mediated phosphorylation of EZH2 regulates the PPAR-γ/TGF-β1 signaling pathway through histone methylation in response to high glucose stimulation. These findings on TGF-β1 regulation are consistent with previous studies, suggesting AMPK activation as a target for diabetic heart failure treatment.

The second concern is based on whether PPAR-γ activation can effectively improve heart failure. Rosiglitazone, a PPAR-γ agonist, was found to inhibit the expression of α-smooth muscle actin, TGF-β1, and type 1 collagen in cardiac fibroblasts exposed to high glucose conditions. In a previous study, pioglitazone attenuated cardiac fibrosis in a murine model [8,9]. However, meta-analyses have demonstrated that the use of thiazolidinedione in diabetes mellitus is associated with increased risk of heart failure [10]. Thiazolidinediones stimulate sodium reabsorption in the distal nephron, which leads to fluid retention and peripheral edema. This effect is linked to a modest but statistically significant increase in the risk of heart failure. Therefore, it is necessary to clarify whether PPAR-γ activation improves only cardiac fibrosis or whether it can improve systolic and diastolic function of the diabetic heart. The potential for fluid retention associated with thiazolidinedione may outweigh the benefits on cardiac fibrosis. Therefore, future studies are needed to investigate whether novel PPAR-γ agonist or coagonist/antagonist of other molecular pathways can improve composite outcomes of heart failure.

EZH2, the primary enzymatic subunit of the polycomb repressive complex 2 (PRC2), functions as a histone methyltransferase, suppressing the transcription of target genes by catalyzing H3K27me3 in a PRC2-dependent manner. H3K-27me3 is a repressive epigenetic marker whose modulation via therapy holds great promise, especially in cancer. Valemetostat, an EZH1–EZH2 (EZH1/2) dual inhibitor, substantially decreased H3K27me3 levels in tumor suppressor genes and effectively restored the epigenome of tumor cells to a state resembling that of healthy tissue. These findings demonstrated the sustained safety and efficacy of valemetostat against human T-cell leukaemia virus type 1 (HTLV-1)-associated aggressive adult T cell leukemia/lymphoma and other lymphomas [11]. In addition to its emerging potential as an anti-cancer agent, the therapeutic potential of an EZH1/2 inhibitor in metabolic diseases should be further explored, especially with regard to ameliorating fibrosis. The observed improvement in cardiac fibrosis using GSK126 (a competitive inhibitor of EZH2) suggests that EZH is a potential therapeutic target for diabetic heart failure.

In conclusion, this study is of considerable significance and delineates potential therapeutic targets for the treatment of diabetic heart failure. It provides direct experimental evidence elucidating the underlying mechanisms and potential therapeutic targets for cardiac fibrosis induced by diabetes: EZH2, AMPK, and PPAR-γ. As EZH2 inhibitors are increasingly recognized as promising treatments for a range of diseases, it is imperative to assess their potential for treating metabolic disorders. The effects and perturbation of molecular pathways of metformin and/or novel AMPK activators should be further studied in diabetic heart failure. Given the extensive history of adverse outcomes associated with PPAR-γ agonists in heart failure, it should be cautiously considered in treating diabetic heart failure.

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Fan Y, Yan Z, Li T, Li A, Fan X, Qi Z, et al. Primordial drivers of diabetes heart disease: comprehensive insights into insulin resistance. Diabetes Metab J 2024;48:19-36.Article PubMed PMC PDF
2. Jankauskas SS, Kansakar U, Varzideh F, Wilson S, Mone P, Lombardi A, et al. Heart failure in diabetes. Metabolism 2021;125:154910.Article PubMed PMC
3. Cho DH, Park SM. Epicardial adipose tissue and heart failure, friend or foe? Diabetes Metab J 2024;48:373-84.Article PubMed PMC PDF
4. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.PubMed
5. Li SS, Pan L, Zhang ZY, Zhou MD, Chen XF, Qian LL, et al. Diabetes promotes myocardial fibrosis via AMPK/EZH2/PPAR-γ signaling pathway. Diabetes Metab J 2024;48:716-29.Article PubMed PMC PDF
6. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013;6:395-402.PubMed
7. Xiao H, Ma X, Feng W, Fu Y, Lu Z, Xu M, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res 2010;87:504-13.PubMed
8. Wei WY, Zhang N, Li LL, Ma ZG, Xu M, Yuan YP, et al. Pioglitazone alleviates cardiac fibrosis and inhibits endothelial to mesenchymal transition induced by pressure overload. Cell Physiol Biochem 2018;45:26-36.Article PubMed PDF
9. Elrashidy RA, Asker ME, Mohamed HE. Pioglitazone attenuates cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. J Cardiovasc Pharmacol Ther 2012;17:324-33.Article PubMed PDF
10. Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 2011;342:d1309.Article PubMed PMC
11. Yamagishi M, Kuze Y, Kobayashi S, Nakashima M, Morishima S, Kawamata T, et al. Mechanisms of action and resistance in histone methylation-targeted therapy. Nature 2024;627:221-8.Article PubMed PMC PDF

Figure & Data

References

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite this Article

Cite this Article: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Targeting Cardiac Fibrosis in Diabetic Heart Failure: The Role of the EZH2, AMPK, and PPAR-γ Pathways (Diabetes Metab J 2024;48:716-29)

Diabetes Metab J. 2024;48(6):1176-1178. Published online November 21, 2024

DOI: https://doi.org/10.4093/dmj.2024.0551

XML Download

Related articles

Targeting Cardiac Fibrosis in Diabetic Heart Failure: The Role of the EZH2, AMPK, and PPAR-γ Pathways (Diabetes Metab J 2024;48:716-29)

About this article

Lee J, Moon JH. Targeting Cardiac Fibrosis in Diabetic Heart Failure: The Role of the EZH2, AMPK, and PPAR-γ Pathways (Diabetes Metab J 2024;48:716-29). Diabetes Metab J. 2024;48(6):1176-1178.

DOI: https://doi.org/10.4093/dmj.2024.0551.

Download citation ↓