Targeting High Glucose-Induced Epigenetic Modifications at Cardiac Levels: The Role of SGLT2 and SGLT2 Inhibitors

Abstract

Background: Sodium-glucose co-transporters inhibitors showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data are reported on their capability to act via epigenetic mechanisms. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors to induce protective effects at the cardiovascular level by acting on DNA methylation. Methods: To better clarify this issue, the effects of empagliflozin on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. Results: Seven days of high glucose treatment induced a significant demethylation in the promoter regions of NF-kB and SOD2 with a consequently high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in promoter regions of analyzed genes. Indeed, empagliflozin prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracts the altered gene expression. The transient SGLT2 gene silencing prevents the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and anti-oxidant effect of empagliflozin in cardiomyocytes. Conclusions: In conclusion, our results demonstrated that empagliflozin, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects.

The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells

“…Therefore, other SGLT2-independent effects of gliflozins must account for their effect on aKlotho in MDCK cells. As a matter of fact, such effects exist and play a role in nephro-and cardioprotection by SGLT2 inhibitors: Among them are antiinflammatory properties (51,52). Accordingly, we observed a small, but statistically significant down-regulation of p65 subunit (encoded by RELA) of pro-inflammatory NFkB transcription factor (53, 54) by canagliflozin, sotagliflozin, and dapagliflozin.…”

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

“…12 Furthermore, SGLT2i may have anti-inflammatory effects (beyond serum urate lowering), including the inhibition of interleukin (IL)-1β, [55][56][57] a key mediator of the inflammatory cascade associated with gout flares, 58 and have also been shown to downregulate IL-6, TNF-α, and MCP-1 as well as C-reactive protein. 59,60 Several observational and 2 post hoc randomized clinical trial analyses, plus a systematic review and meta-analysis, 61 found that SGLT2i are associated with a lower risk of newonset gout or heterogenous related end points (including gout medication initiation), among patients with T2D or heart failure. 22,24,25,62,63 For example, SGLT2i initiation was associated with a 34% and 40% lower risk of incident gout, compared with initiation of DPP-4i and GLP1-RA, respectively.…”

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Harms or Unexpected Benefits?

“…The ratio of HDL-C to LDL-C remained unchanged because the peaks in HDL and LDL were very similar [53,55]. Another set of findings from a study demonstrated that empagliflozin, primarily acting on SGLT2, prevented DNA methylation changes brought on by high glucose [56]. These findings also provided evidence of a new mechanism by which SGLT2 inhibitors can exert cardio-beneficial effects [56].…”

“…Another set of findings from a study demonstrated that empagliflozin, primarily acting on SGLT2, prevented DNA methylation changes brought on by high glucose [56]. These findings also provided evidence of a new mechanism by which SGLT2 inhibitors can exert cardio-beneficial effects [56]. Dapagliflozin is safe and improves outcomes regardless of baseline NT-proBNP concentrations in HF with mildly reduced Ejection Fraction (HFmrEF) or HF with preserved Ejection Fraction (HFpEF), with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations according to the findings of another large trial [57].…”