Xiaodong Peng1,2, Linling Li3, Rong Lin4, Xuesi Wang1,2, Xinmeng Liu1,2, Yukun Li1,2, Changsheng Ma1,2, Yanfei Ruan5,6, Nian Liu7,8. 1. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 2. National Clinical Research Center for Cardiovascular Diseases, Beijing, China. 3. Department of Cardiology, Beijing ChuiYangLiu Hospital, Beijing, China. 4. North China Medical & Health Group XingTai Genernal Hospital, Xingtai, China. 5. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. ruanyanfei@hotmail.com. 6. National Clinical Research Center for Cardiovascular Diseases, Beijing, China. ruanyanfei@hotmail.com. 7. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. liunian1973@hotmail.com. 8. National Clinical Research Center for Cardiovascular Diseases, Beijing, China. liunian1973@hotmail.com.
Abstract
PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner. METHODS: Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 μmol/L). RESULTS: In the absence of ouabain, 1 μmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 μmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 μmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 μmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 μmol/L cariporide) abolished the effects of empagliflozin. CONCLUSION: Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.
PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner. METHODS: Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 μmol/L). RESULTS: In the absence of ouabain, 1 μmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 μmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 μmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 μmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 μmol/L cariporide) abolished the effects of empagliflozin. CONCLUSION: Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.
Authors: Juan Antonio Requena-Ibáñez; Carlos G Santos-Gallego; Anderly Rodriguez-Cordero; Ariana P Vargas-Delgado; Donna Mancini; Samantha Sartori; Farah Atallah-Lajam; Chiara Giannarelli; Frank Macaluso; Anuradha Lala; Javier Sanz; Valentin Fuster; Juan José Badimon Journal: JACC Heart Fail Date: 2021-08 Impact factor: 12.035