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

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

  • Biomed Pharmacother. 2025 Oct 22:192:118670. doi: 10.1016/j.biopha.2025.118670.
Xiaoling Li 1,  Mengnan Wang 2,  Jil Seehaber 3,  Charlotte Stuhldreier 3,  Yumna A Butt 2,  Marta Z Pacia 4,  Markus W Hollmann 2,  Benedikt Preckel 2,  Martin Albrecht 5,  Coert J Zuurbier 2,  Nina C Weber 6
Affiliations

Affiliations

  • 1 University Medical Center, Department of Anesthesiology - Laboratory of Experimental Intensive Care and Anesthesiology-L. E. I. C. A, Amsterdam Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 University Medical Center, Department of Anesthesiology - Laboratory of Experimental Intensive Care and Anesthesiology-L. E. I. C. A, Amsterdam Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands.
  • 3 University Medical Center, Department of Anesthesiology - Laboratory of Experimental Intensive Care and Anesthesiology-L. E. I. C. A, Amsterdam Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
  • 4 Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University in Krakow, Bobrzynskiego 14, Krakow 30-348, Poland.
  • 5 Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
  • 6 University Medical Center, Department of Anesthesiology - Laboratory of Experimental Intensive Care and Anesthesiology-L. E. I. C. A, Amsterdam Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. Electronic address: N.C.Hauck@amsterdamumc.nl.
PMID: 41130096 DOI: 10.1016/j.biopha.2025.118670
Abstract

Background: 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 CA2+, VE-cadherin phosphorylation, and inflammatory activation. We hypothesized that EMPA prevents OSS-induced dysfunction by inhibiting ROS through the NHE1/NCX/CA2+ axis or Piezo1.

Methods: 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 CA2+ 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.

Results: EMPA restored OSS-induced increases in ROS, CA2+, 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.

Conclusions: EMPA prevents OSS induced ROS generation by the inhibition of the NHE1/NCX/CA2+ 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.

Keywords

Calcium; Empagliflozin; Oscillatory shear stress; Sodium-calcium exchanger; Sodium-hydrogen exchanger 1.

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