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- Title
Comparison of the effects of empagliflozin and sotagliflozin on a zebrafish model of diabetic heart failure with reduced ejection fraction.
- Authors
Kim, Inho; Cho, Hyun-Jai; Lim, Soo; Seok, Seung Hyeok; Lee, Hae-Young
- Abstract
The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) and dual SGLT1/2 inhibitor sotagliflozin (SOTA) are emerging as heart failure (HF) medications in addition to having glucose-lowering effects in diabetes mellitus (DM). However, the precise mechanism underlying this cardioprotective effect has not yet been elucidated. Here, we evaluated the effects of EMPA and SOTA in a zebrafish model of DM combined with HF with reduced ejection fraction (DM-HFrEF). To compare the effects of the two drugs, survival, locomotion, and myocardial contractile function were evaluated. The structural binding and modulating effects of the two medications on sodium-hydrogen exchanger 1 (NHE1) were evaluated in silico and in vitro. DM-HFrEF zebrafish showed impaired cardiac contractility and decreased locomotion and survival, all of which were improved by 0.2–5 μM EMPA or SOTA treatment. However, the 25 μM SOTA treatment group had worse survival rates and less locomotion preservation than the EMPA treatment group at the same concentration, and pericardial edema and an uninflated swim bladder were observed. SOTA, EMPA and cariporide (CARI) showed similar structural binding affinities to NHE1 in a molecular docking analysis and drug response affinity target stability assay. In addition, EMPA, SOTA, and CARI effectively reduced intracellular Na+ and Ca2+ changes through the inhibition of NHE1 activity. These findings suggest that both EMPA and SOTA exert cardioprotective effects in the DM-HFrEF zebrafish model by inhibiting NHE1 activity. In addition, despite the similar cardioprotective effects of the two drugs, SOTA may be less effective than EMPA at high concentrations. Diabetes: Glucose-lowering drugs protect against heart failure Two existing drugs used to lower glucose in patients with diabetes also reduce the chances of heart failure by blocking the excessive activity of a protein involved in transport of molecules across membranes. The drugs empagliflozin and sotagliflozin, which inhibit sodium-glucose transporters in diabetes, also help protect against heart failure, but the mechanisms are unclear. Hae-Young Lee and Seung Hyeok Seok at Seoul National University, South Korea, and co-workers examined the cardio-protective effects of the drugs on zebrafish models of diabetic heart failure.They focused on sodium-hydrogen exchanger 1 (NHE1), which regulates sodium and hydrogen levels to maintain pH balance, and is increased in the heart ventricle tissue of patients with heart failure. The team found that both drugs blocked NHE1 activity, while also targeting sodium-glucose transporters. Empagliflozin was particularly effective at protecting the heart in this way.
- Publication
Experimental & Molecular Medicine EMM, 2023, Vol 55, Issue 6, p1174
- ISSN
1226-3613
- Publication type
Article
- DOI
10.1038/s12276-023-01002-3