Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
Exp Mol Med. 2023 Jun;55(6):1174-1181. doi: 10.1038/s12276-023-01002-3. Epub 2023 Jun 1.
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 Ca 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.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂恩格列净（EMPA）和双重 SGLT1/2 抑制剂索格列净（SOTA）除了具有降低糖尿病（DM）患者血糖的作用外，还可作为心力衰竭（HF）的治疗药物。然而，这种心脏保护作用的确切机制尚未阐明。在这里，我们在伴有射血分数降低的心力衰竭（DM-HFrEF）的 DM 斑马鱼模型中评估了 EMPA 和 SOTA 的作用。为了比较这两种药物的作用，评估了它们对生存、运动和心肌收缩功能的影响。通过计算机模拟和体外实验评估了这两种药物对钠离子-氢交换体 1（NHE1）的结构结合和调节作用。DM-HFrEF 斑马鱼表现出心肌收缩力受损、运动能力降低和存活率降低，所有这些都可以通过 0.2-5 μM 的 EMPA 或 SOTA 治疗得到改善。然而，与相同浓度的 EMPA 治疗组相比，25 μM 的 SOTA 治疗组的存活率较低，运动能力保存较差，并且观察到心包水肿和未充气的鳔。分子对接分析和药物反应亲和力靶标稳定性测定显示，SOTA、EMPA 和 cariporide（CARI）与 NHE1 具有相似的结构结合亲和力。此外，EMPA、SOTA 和 CARI 通过抑制 NHE1 活性有效减少了细胞内 Na 和 Ca 的变化。这些发现表明，EMP A 和 SOTA 通过抑制 NHE1 活性对 DM-HFrEF 斑马鱼模型发挥心脏保护作用。此外，尽管这两种药物的心脏保护作用相似，但 SOTA 在高浓度时的效果可能不如 EMPA。
