Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.
Pharmacol Res. 2020 Aug;158:104870. doi: 10.1016/j.phrs.2020.104870. Epub 2020 May 17.
Sodium-glucose co-transporter 2 (SGLT2) were originally developed as kidney-targeting anti-diabetic drugs. However, due to their beneficial cardiac off-target effects (as SGLT2 is not expressed in the heart), these antagonists currently receive intense clinical interest in the context of heart failure (HF) in patients with or without diabetes mellitus (DM). Since the mechanisms by which these beneficial effects are mediated are still unclear yet, inflammation that is present in DM and HF has been proposed as a potential pharmacological intervention strategy. Therefore, we tested the hypothesis that the SGLT2 inhibitor, empagliflozin, displays anti-inflammatory potential along with its glucose-lowering property.
Lipopolysaccharide (LPS) was used to induce inflammation in vitro and in vivo. In cardiomyocytes and macrophages empagliflozin attenuated LPS-induced TNFα and iNOS expression. Analysis of intracellular signalling pathways suggested that empagliflozin activates AMP kinase (AMPK) in both cell types with or without LPS-treatment. Moreover, the SGLT2 inhibitor increased the expression of anti-inflammatory M2 marker proteins in LPS-treated macrophages. Additionally, empagliflozin-mediated AMPK activation prevented LPS-induced ATP/ADP depletion. In vivo administration of LPS in mice impaired cardiac contractility and aortic endothelial relaxation in response to acetylcholine, whereby co-administration of empagliflozin preserved cardiovascular function. These findings were accompanied by improved cardiac AMPK phosphorylation and ATP/ADP, reduced cardiac iNOS, plasma TNFα and creatine kinase MB levels.
Our data identify a novel cardio protective mechanism of SGLT2 inhibitor, empagliflozin, suggesting that AMPK activation-mediated energy repletion and reduced inflammation contribute to the observed cardiovascular benefits of the drug in HF.
钠-葡萄糖协同转运蛋白 2（SGLT2）最初被开发为针对肾脏的抗糖尿病药物。然而，由于其对心脏的有益非靶向作用（因为 SGLT2 不在心脏中表达），这些拮抗剂目前在伴有或不伴有糖尿病的心力衰竭（HF）患者中受到强烈的临床关注。由于介导这些有益作用的机制尚不清楚，因此，炎症被认为是 DM 和 HF 中潜在的药理学干预策略。因此，我们测试了 SGLT2 抑制剂恩格列净除了降低血糖作用外，还具有抗炎潜力的假设。
脂多糖（LPS）用于体外和体内诱导炎症。在心肌细胞和巨噬细胞中，恩格列净可减轻 LPS 诱导的 TNFα 和 iNOS 表达。对细胞内信号通路的分析表明，恩格列净在有或没有 LPS 处理的情况下激活两种细胞类型中的 AMP 激酶（AMPK）。此外，SGLT2 抑制剂增加了 LPS 处理的巨噬细胞中抗炎 M2 标志物蛋白的表达。此外，恩格列净介导的 AMPK 激活可防止 LPS 诱导的 ATP/ADP 耗竭。在 LPS 处理的小鼠体内给药会损害心肌收缩力和对乙酰胆碱的主动脉内皮松弛，而恩格列净的共同给药可维持心血管功能。这些发现伴随着心脏 AMPK 磷酸化和 ATP/ADP 的改善，心脏 iNOS、血浆 TNFα 和肌酸激酶 MB 水平的降低。
我们的数据确定了 SGLT2 抑制剂恩格列净的一种新的心脏保护机制，表明 AMPK 激活介导的能量补充和炎症减少有助于该药物在 HF 中的观察到的心血管益处。
