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Background  Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I 2  (PGI 2 ) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI 2  synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI 2  stimulation in endothelial cells.    Methods and Results  Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI 2  accumulation in the culture media was measured. Cilostazol increased PGI 2  synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI 2  synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI 2  synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI 2  synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) γ, and phospholipase C (PLC) ε, suppressed cilostazol-induced PGI 2  synthesis.    Conclusions  The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI 2  synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCε/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kγ, resulting in synergistically induced PGI 2  synthesis.

plos one

Cilostazol Induces PGI2 Production via Activation of the Downstream Epac-1/Rap1 Signaling Cascade to Increase Intracellular Calcium by PLCε and to Activate p44/42 MAPK in Human Aortic Endothelial Cells