Work

Sodium glucose co-transporter 2 inhibitor empagliflozin prevents endothelial dysfunction induced by oscillatory shear stress

Year: 2025

Type: article

Abstract: Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor, exhibits endothelial protective effects under disturbed flow conditions. Oscillatory shear stress (OSS) induces endothelial dysfunction via increased reactive oxygen species (ROS), intracellular Ca 2+ , VE-cadherin phosphorylation, and inflammatory activation. We hypothesized that EMPA prevents OSS-induced dysfunction by inhibiting ROS through the NHE1/NCX/Ca 2+ axis or Piezo1. Human coronary artery endothelial cells (HCAECs) were pretreated with EMPA and exposed to LSS or OSS. Mechanistic studies included ROS scavenger NAC, calcium chelator BAPTA-AM, NHE1 inhibitor cariporide, NCX inhibitor ORM-10962, and Piezo1 knockdown. ROS, NO bioavailability, and Ca 2+ were measured using live-cell imaging. VE-cadherin and ICAM-1 were evaluated by immunostaining; phosphorylation of VE-cadherin, SFK, ERK1/2, and Piezo1 was assessed by Western blot. Ex vivo en face staining of mouse aortas analyzed EMPA’s effect on endothelial SOD1 expression. EMPA restored OSS-induced increases in ROS, Ca 2+ , VE-cadherin phosphorylation, ICAM-1, and monocyte transmigration (all P < 0.05). Piezo1 knockdown or inhibitors of NHE1/NCX reduced ROS, with no additive effect when combined with EMPA, suggesting a shared pathway. NAC restored VE-cadherin but not ICAM-1. EMPA increased endothelial SOD1 expression in aortic arches, confirming the translational relevance of in vitro findings. EMPA prevents OSS induced ROS generation by the inhibition of the NHE1/NCX/Ca 2+ axis. The suppression of OSS-induced ROS generation by EMPA contributes to improved endothelial barrier function of endothelial cells but has limited effect on the inflammatory response in HCAECs subjected to OSS. • Disturbed flow exerts adverse effects on vascular endothelium and is associated with myocardial ischemia. • Empagliflozin alleviates oscillatory shear stress induced oxidative stress in both in vitro and ex vivo models. • Empagliflozin exerts antioxidative effects in a Ca 2+ -dependent manner. • Empagliflozin reduces disturbed flow-induced oxidative stress by inhibiting Na + /H + exchanger 1 and Na + /Ca 2+ exchanger.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118670