Cilostazol Induces eNOS and TM Expression via Activation with Sirtuin 1/Krüppel-like Factor 2 Pathway in Endothelial Cells

Abstract

Cilostazol was suggested to be beneficial to retard in-stent atherosclerosis and prevent stent thrombosis. However, the mechanisms responsible for the beneficial effects of cilostazol are not fully understood. In this study, we attempted to verify the mechanism of the antithrombotic effect of cilostazol. Human umbilical vein endothelial cells (HUVECs) were cultured with various concentrations of cilostazol to verify its impact on endothelial cells. KLF2, silent information regulator transcript-1 (SIRT1), endothelial nitric oxide synthase (eNOS), and endothelial thrombomodulin (TM) expression levels were examined. We found cilostazol significantly activated KLF2 expression and KLF2-related endothelial function, including eNOS activation, Nitric oxide (NO) production, and TM secretion. The activation was regulated by SIRT1, which was also stimulated by cilostazol. These findings suggest that cilostazol may be capable of an antithrombotic and vasculoprotective effect in endothelial cells.

Transcriptomic analysis reveals Cilostazol's role in ameliorating cardiovascular disease: Inhibition of monocyte-to-macrophage differentiation and reduction of endothelial cell reactive oxygen species production

“…A notable increase in stromal cells, including endothelial cells and adipocytes, implies a synergistic approach to cardiovascular health [ 42 ]. Our previous study consistently supported the activation of KLF2 expression and its associated endothelial functions (eNOS activation, NO production, and secretion) by cilostazol [ 24 ]. Such evidence emphasizes its ability to inhibit oxidative stress-induced premature senescence and Sirt1 upregulation in human endothelial cells [ 43 ].…”

“…Our previous research focusing on endothelial cells discovered that both cilostazol and ginkgo biloba extract could enhance the expressions of endothelial cell thrombomodulin (TM) and endothelial NO synthase (eNOS) by activating the Krüppel-like factor 2 (KLF2) axis. This activation subsequently increased the endothelial cells' ability to dissolve blood clots [ [23] , [24] , [25] ]. These findings provide valuable insights into the potential therapeutic applications of cilostazol and ginkgo biloba extract in cardiovascular health.…”

Effects of a Phosphodiesterase inhibitor on the Browning of Adipose Tissue in Mice

“…Cilostazol is an antiplatelet drug that inhibits both primary and secondary platelet aggregation in response to ADP, collagen, epinephrine, and arachidonic acid [ 17 ]. The antiplatelet, anti-inflammatory, and vasodilator actions of cilostazol improve the claudication intermittent symptoms via the cAMP-induced inhibition of PDE [ 33 , 34 , 35 ]. Furthermore, there is evidence to support the role of PDE inhibition in improving systemic metabolism.…”

Generation of Functional Cardiomyocytes from Human Gastric Fibroblast-Derived Induced Pluripotent Stem Cells

“…The Western blot assay had been performed in our previous work [ 7 ]. Protein was collected by scraping and carried out on ice in RIPA buffer and a protease-inhibiting cocktail (Complete Roche Molecular Biochemi-cals, Almere, The Netherlands).…”