Faculty of Medicine, Gaziantep University, Gaziantep, Turkey.
Department of Medical Pharmacology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey.
Eur J Pharmacol. 2024 Nov 5;982:176934. doi: 10.1016/j.ejphar.2024.176934. Epub 2024 Aug 23.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors produce cardioprotective effects on heart failure (HF), even in the absence of diabetes. However, the underlying mechanisms of this cardioprotective effect remain unexplored. The purpose of this study was to examine the effects of SGLT2 inhibitors on serum MOTS-c, humanin levels, nitrosative stress, and ferroptosis parameters in diabetic patients with HF with reduced ejection fraction (HFrEF). A total of 74 adult diabetic patients with HFrEF and 37 healthy controls were included in this prospective study. Half of the patients were using SGLT2 inhibitors (empagliflozin or dapagliflozin) for at least two months. Serum nitric oxide and 3-nitrotyrosine levels were markedly higher in diabetic patients with HFrEF than the control (P < 0.001), but these elevations were inhibited with SGLT2 inhibitors. Although SGLT2 inhibitors had no marked effect on humanin levels, they significantly augmented MOTS-c levels when compared to the control. SGLT2 inhibitors augmented GPX4 but inhibited ACSL4 levels when compared to diabetic patients with HF. However, TFRC levels were increased in the patient group (P < 0.001 for all) but not modified with SGLT2 inhibitors. Our results suggest that increased nitrosative stress is significantly depressed by SGLT2 inhibitors. This study was the first to show that SGLT2 inhibitors can stimulate MOTS-c, but not humanin, in diabetic patients with HFrEF. SGLT2 inhibitors reduced ferroptosis through elevation of GPX4 and suppression of ACSL4 levels. Our data suggest that SGLT2 inhibitors could produce cardioprotective effects through relieving ferroptosis, inhibiting nitosative stress, and stimulating mitochondrial MOTS-c release.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂对心力衰竭（HF）具有心脏保护作用，即使在没有糖尿病的情况下也是如此。然而，这种心脏保护作用的潜在机制仍未得到探索。本研究旨在研究 SGLT2 抑制剂对伴有射血分数降低的心力衰竭（HFrEF）的糖尿病患者血清 MOTS-c、人源素、硝化应激和铁死亡参数的影响。本前瞻性研究共纳入 74 名成年糖尿病 HFrEF 患者和 37 名健康对照者。其中一半患者至少使用 SGLT2 抑制剂（恩格列净或达格列净）治疗两个月。与对照组相比，糖尿病 HFrEF 患者的血清一氧化氮和 3-硝基酪氨酸水平明显升高（P<0.001），但 SGLT2 抑制剂可抑制这些升高。尽管 SGLT2 抑制剂对人源素水平没有明显影响，但与对照组相比，它们显著增加了 MOTS-c 水平。与 HF 患者相比，SGLT2 抑制剂增加了 GPX4 但抑制了 ACSL4 水平。然而，TRFC 水平在患者组中升高（所有 P<0.001），但 SGLT2 抑制剂并未改变。我们的结果表明，硝化应激显著受 SGLT2 抑制剂抑制。本研究首次表明，SGLT2 抑制剂可刺激伴有 HFrEF 的糖尿病患者的 MOTS-c，但不能刺激人源素。SGLT2 抑制剂通过升高 GPX4 和抑制 ACSL4 水平来减少铁死亡。我们的数据表明，SGLT2 抑制剂可通过缓解铁死亡、抑制硝化应激和刺激线粒体 MOTS-c 释放来产生心脏保护作用。
