Cilostazol Improves Hyperglycemia-Induced Impairment of Angiogenesis by Stimulating Adiponectin/Adiponectin Receptor1/Sirtuin1

Abstract Background: Cilostazol is an antiplatelet agent with vasodilating effects that functions by increasing the intracellular concentration of cyclic adenosine monophosphate. However, the effect of cilostazol on adiponectin is still unclear. Purpose: We investigated the effects of cilostazol on adiponectin/adiponectin receptors and the Sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling pathway to prevent high glucose (HG)-induced impairment of angiogenesis in vitro and in vivo. Methods and Results: Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cocultured in HG conditions. Adiponectin concentrations in the supernatant were significantly increased when HASMCs were treated with cilostazol but not significantly changed when only HUVECs were treated with cilostazol. Cilostazol treatment restored the expression of the adipoR1 and SIRT1 proteins and upregulated the phosphorylation of AMPKa1 in the HUVECs treated with HG but not adipoR2. Cilostazol prevented apoptosis and stimulated proliferation, chemotactic motility and capillary-like tube formation in HG-treated HUVECs through the adipoR1/AMPK/SIRT1 signaling pathway. In cilostazol-treated mice, recovery of the blood flow ratio after hindlimb ischemia and circulating CD34+CD45dim cells were significantly attenuated by adipoR1 knockdown but not adipoR2 knockdown. The expression of SIRT1, phosphorylation of AMPKa1/acetyl-CoA carboxylase and Akt/endothelial nitric oxide synthase in ischemic muscles were significantly attenuated by gene knockdown of adipoR1. Conclusions: Cilostazol prevents HG-induced endothelial dysfunction in vascular endothelial cells and enhances angiogenesis in hyperglycemic mice by upregulating the expression of adiponectin/adipoR1 and its SIRT1/AMPK downstream signaling pathway.