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Review
. 2024 May;29(5):73.
doi: 10.3892/mmr.2024.13197. Epub 2024 Mar 15.

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

Bixian Chen #  1 , Jing Guo #  1 , Hongmei Ye  1 , Xinyu Wang  1 , Yufei Feng  2
Affiliations
Review

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

Bixian Chen et al. Mol Med Rep. 2024 May.

Abstract

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis and dysregulation of signaling pathways. These changes in heart structure and/or function ultimately result in heart failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the cardiac benefits of sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed to treat type 2 diabetes mellitus. SGLT2is include empagliflozin and dapagliflozin, which are listed as guideline drugs in the 2021 European Guidelines for Heart Failure and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines for Heart Failure Management. In recent years, multiple studies using animal models have explored the mechanisms by which SGLT2is prevent cardiac remodeling. This article reviews the role of SGLT2is in cardiac remodeling induced by different etiologies to provide a guideline for further evaluation of the mechanisms underlying the inhibition of pathological cardiac remodeling by SGLT2is, as well as the development of novel drug targets.

Keywords: SGLT2 inhibitors; cardiac fibroblasts; cardiac remodeling; molecular mechanisms; myocardial hypertrophy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Possible role and mechanism of SGLT2is in inhibiting pathological cardiac remodeling. SGLT2is, sodium-glucose cotransporter type 2 inhibitors; JAK, Janus kinase; STAT, signal transducer and activator of transcription; SGK1, Serum/glucocorticoid regulated kinase 1; sGC, soluble guanylate cyclase enzyme; cGMP, cyclic guanosine monophosphate; PKG, cGMP-dependent protein kinase.
Figure 2.
Figure 2.
Role of SGLT2is in inhibiting pathological cardiac remodeling. SGLT2is, sodium-glucose cotransporter type 2 inhibitors; AMPK, AMP-activated protein kinase; NHE1, Na+/H+ exchanger 1; SIRT1, sirtuin-1; XO, xanthine oxidase; SERCA2, sarco(endo)plasmic reticulum calcium-ATPase 2; CaMKII, calmodulin-dependent kinase II; HIF1-α, hypoxia-inducible factor 1-α; SGK1, serum and glucocorticoid-induced protein kinase 1.
Figure 3.
Figure 3.
Indirect effect of SGLT2is on pathological cardiac remodeling by inhibiting the crosstalk between inflammation and oxidative stress. SGLT2is, sodium-glucose cotransporter type 2 inhibitors; ROS, reactive oxygen species; IκB, inhibitor of NF-κB.
Figure 4.
Figure 4.
Schematic of the regulatory mechanisms of SGLT2is in pathological cardiac remodeling. SGLT2is, sodium-glucose cotransporter type 2 inhibitors; HMGB1, high mobility group box 1; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species; AMPK, AMP-activated protein; Nrf2, nuclear factor erythroid 2-related factor 2; NF-κB, nuclear factor-B; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; CD36, cluster of differentiation 36; SGK1, serum and glucocorticoid-induced protein kinase 1; NHE1, Na+/H+ exchanger 1; SIRT1, sirtuin-1; XO, xanthine oxidase; SERCA2, sarco(endo)plasmic reticulum calcium-ATPase 2; CaMKII, calmodulin-dependent kinase II; HIF1-α, hypoxia-inducible factor 1-α; sGC, soluble guanylate cyclase enzyme; cGMP, cyclic guanosine monophosphate; PKG, cGMP-dependent protein kinase; eIF2, eukaryotic initiation factor 2; PERK, protein kinase RNA-like ER kinase; CHOP, C/EBP homologous protein; ATF4, activating transcription factor 4; ULK1, UNC-52-like kinase 1; GSK3β, glycogen synthase kinase 3β; p70S6K, 70 kDa ribosomal protein S6 kinase; 4EBP1, 4E-binding protein 1; SLC7A11, solute carrier family 7a member 11; PPARα, peroxisome proliferator-activated receptor α; NCX, sodium-calcium exchangers; TFR1, transferrin receptor 1; FTN-H, ferritin heavy-chain; AP-1, activator protein-1; EPO, erythropoietin; NETs, neutrophil extracellular traps; HO-1, heme oxygenase-1; TRL4, toll-like receptor 4; MyD88, myeloid differentiation primary response 88; NLRP3, NLR family pyrin domain containing 3; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; OXPHOS, oxidative phosphorylation; Drp1, dynamin-related protein 1; eNOS, endothelial nitric oxide synthase; Fis-1, fission 1; MFN-1, mitofusin 1; CPT1, carnitine O-palmitoyltransferase 1; Opa1, optic atrophy 1; PHD2, prolyl hydroxylase 2; VEGFA, vascular endothelial growth factor A.
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Grants and funding

This work was supported by the National Natural Science Foundation of China (grant no. 82104156).