Tropisetron Attenuates High-Glucose-Induced Vascular Endothelial Dysfunction Via Inhibition of Calcineurin/Nfat Signalling Publisher Pubmed



Barzegarfallah A^{1, 2} ; Ghaffaribohlouli P² ; Nadjafi S³ ; Razmi A⁴ ; Dehpour AR⁵ ; Ghaffarianbahraman A⁶ ; Alimoradi H^{1, 2} ; Shafiei M¹ Show Affiliations
Source: European Journal of Pharmacology Published:2025

Abstract

Vascular endothelial dysfunction (VED) is considered an important initiating factor in pathogenesis of diabetic vascular disease. In this process, oxidative insult, cellular hypertrophy, and activation of the calcineurin/nuclear factor of activated T-cell (NFAT) pathway play key roles. Herein, we investigated the effects of tropisetron (TRS), a calcineurin inhibitor, on high glucose (HG)-induced hypertrophy and apoptosis in human umbilical vein endothelial cells (HUVECs). To this end, HUVECs and chorioallantoic membranes (CAMs) were exposed to HG with or without TRS or cyclosporine A (CsA), and the effects of the treatments were evaluated on oxidative stress generation, cell number (proliferation and apoptosis), cell size (hypertrophy), and vessel formation. We also explored the possible role of calcineurin-NFAT signalling in the potential protective effects of TRS on hypertrophy and apoptosis associated with HG. The average size and protein content of the cells exposed to HG for 48h were significantly increased compared with normal glucose (NG). HG significantly increased apoptosis, altered the cell cycle, and elevated oxidative and nitrosative stress in HUVECs. Further, exposing cells to HG resulted in elevated calcineurin activity and NFATc1 translocation to the nuclei. HG also caused a significant decrease in the formation of new blood vessels in CAMs. Inhibition of calcineurin/NFAT pathway by TRS or CsA protected against these pathological changes. Our data demonstrated that inhibition of calcineurin/NFAT signalling by TRS, as a safe calcineurin inhibitor, may ameliorate HG-induced VED. Further in vivo and clinical studies are required to fully determine the protective effects of TRS against VED in diabetes. © 2025 Elsevier B.V.