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Background: Empagliflozin (EMPA) attenuates inflammation-induced ROS generation in static endothelial cells through inhibition of sodium hydrogen exchanger 1 (NHE1) and modulation of ion homeostasis. We hypothesize that EMPA will alleviate TNF-α stimulated endothelial dysfunction under flow conditions, and that this might be mediated by NHE1 and intracellular Ca 2+ ., Methods: Human coronary artery endothelial cells were pre-treated with EMPA or vehicle before starting flow with or without TNF-α. Intracellular Ca 2+ was recorded for 5 min at the start of flow. ROS generation and NO bioavailability, Piezo-1, cytokines, adhesion molecules, VE-cadherin and eNOS were detected after 6 h. BAPTA-AM was applied to chelate intracellular Ca 2+ and NHE1 was knocked down with specific siRNA., Results: Under flow conditions, EMPA inhibited ROS production and [Ca 2+ ] increase in cells exposed to TNF-α (P < 0.05). BAPTA-AM and NHE1 knockdown both reduced ROS generation (P < 0.05), and genetical inhibition of NHE1 led to reduction of intracellular [Ca 2+ ] in HCAECs receiving TNF-α (P < 0.05). Yet, EMPA showed no effect on the increased cytokine production, adhesion molecule expression and phosphorylation of eNOS in endothelial cells exposed to TNF-α., Conclusion: EMPA mitigates increased ROS production and impaired NO bioavailability in TNF-α stimulated cells under flow. The anti-oxidative effect of EMPA is mediated by the decreased intracellular [Ca 2+ ] following NHE1 inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)