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

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.