Cilostazol Protects Endothelial Cells Against Lipopolysaccharide-Induced Apoptosis Through ERK1/2- and P38 MAPK-Dependent Pathways

Abstract

Background/AimsWe examined the effects of cilostazol on mitogen-activated protein kinase (MAPK) activity and its relationship with cilostazol-mediated protection against apoptosis in lipopolysaccharide (LPS)-treated endothelial cells.MethodsHuman umbilical vein endothelial cells (HUVECs) were exposed to LPS and cilostazol with and without specific inhibitors of MAPKs; changes in MAPK activity in association with cell viability and apoptotic signaling were investigated.ResultsCilostazol protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c, and subsequent activation of caspases, stimulating extracellullar signal-regulated kinase (ERK1/2) and p38 MAPK signaling, and increasing phosphorylated cAMP-responsive element-binding protein (CREB) and Bcl-2 expression, while suppressing Bax expression. These cilostazol-mediated cellular events were effectively blocked by MAPK/ERK kinase (MEK1/2) and p38 MAPK inhibitors.ConclusionsCilostazol protects HUVECs against LPS-induced apoptosis by suppressing mitochondria-dependent apoptotic signaling. Activation of ERK1/2 and p38 MAPKs, and subsequent stimulation of CREB phosphorylation and Bcl-2 expression, may be responsible for the cellular signaling mechanism of cilostazol-mediated protection.

Cilostazol Reduces the Risk of Hemorrhagic Infarction After Administration of Tissue-Type Plasminogen Activator in a Murine Stroke Model

“…49,50 The vasculoprotective effect of cilostazol was also shown in other studies in which cilostazol suppressed endothelial hyperpermeability by inhibiting redistribution of the actinbased cytoskeleton 51 and protected endothelial cells against lipopolysaccharide-induced apoptosis by the activation of MAP kinase. 52 These findings indicate that the beneficial effect of cilostazol on cerebral hemorrhage might be achieved, at least in part, through suppression of endothelial injury after thrombolysis with tPA injection. Consistent with these findings, cilostazol-treated mice displayed retention of vascular density in ischemic cerebral cortex after tPA treatment, whereas aspirin did not prevent reduction in the number of cerebral microvessels.…”

“…In the current study, we used 1 dose of cilostazol. Because both antiplatelet and vasculoprotective activity of cilostazol are known to be dose-dependent, [52][53][54] further study will be necessary to determine the optimal dose of cilostazol to suppress cerebral hemorrhage after tPA treatment.…”

Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α

“…It also displayed the protective effects against transient focal cerebral ischemia [6] and chronic cerebral hypo perfusion injury [7]. In vitro studies found that cilastozol could prevent the lipopolysaccharide (LPS)-induced apoptosis in HUVECs through mitochondrial pathways [8]. But the effects of cilostazol on mitochondria in endothelial cells remain unknown.…”

Effect of arazyme on the lipopolysaccharide-induced inflammatory response in human endothelial cells

“…Previous studies have identified novel inhibitory materials against the inflammatory response in endothelial cells such as Ecklonia cava extracts and cilostazol (9,11). The current study, focused on elucidating the effect of arazyme on the inflammatory response in HUVECs induced by LPS.…”

“…These mechanisms contribute to endothelial dysfunction and may evoke endothelial cell-associated diseases. A number of studies have attempted to identify methods to protect against the inflammatory response and endothelial cell death (9)(10)(11). In the current study, the role of arazyme in the LPS-mediated inflammatory response in HUVECs was investigated.…”