Cilostazol Enhances Mobilization of Circulating Endothelial Progenitor Cells and Improves Endothelium-Dependent Function in Patients at High Risk of Cardiovascular Disease

Abstract

This is the first study to investigate the vasculoangiogenic effects of cilostazol on endothelial progenitor cells (EPCs) and flow-mediated dilatation (FMD) in patients at high risk of cardiovascular disease (CVD). This double-blind, placebo-controlled study included 71 patients (37 received 200 mg/d cilostazol and 34 received placebo for 12 weeks). Use of cilostazol, but not placebo, significantly increased circulating EPC (kinase insert domain receptor(+)CD34(+)) counts (percentage changes: 149.0% [67.9%-497.8%] vs 71.9% [-31.8% to 236.5%], P = .024) and improved triglyceride and high-density lipoprotein cholesterol levels (P = .002 and P = .003, respectively). Plasma levels of vascular endothelial growth factor (VEGF)-A165 and FMD significantly increased (72.5% [32.9%-120.4%] vs -5.8% [-46.0% to 57.6%], P = .001; 232.8% ± 83.1% vs -46.9% ± 21.5%, P = .003, respectively) in cilostazol-treated patients. Changes in the plasma triglyceride levels significantly inversely correlated with the changes in the VEGF-A165 levels and FMD. Cilostazol significantly enhanced the mobilization of EPCs and improved endothelium-dependent function by modifying some metabolic and angiogenic markers in patients at high risk of CVD.

Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9

“…This post hoc analysis was performed using two previous prospective, double-blind, randomized, placebo-controlled trials, which consecutively enrolled eligible patients with PAD ( n = 44; started in January 2012 and completed in September 2013; cohort 1: ClinicalTrials.gov identifier: NCT01952756) or at high risk of CVD without pre-existing atherosclerotic disease ( n = 71; started in January 2013 and completed in August 2014; cohort 2: ClinicalTrials.gov identifier: NCT02194686). The results of both studies have been published [ 19 , 20 ]. The detailed inclusion and exclusion criteria were described previously [ 19 , 20 ].…”

“…Cilostazol, a phosphodiesterase 3 inhibitor, is licensed for treatment of patients with PAD and intermittent claudication owing to its antiplatelet and vasodilatory effects [ 18 – 20 ]. Recently, we and other researchers found that this compound has beneficial effects on metabolic parameters, angiogenesis, numbers and functions of circulating human early EPCs in vitro [ 18 , 21 – 24 ], in vivo [ 18 , 21 – 24 ], and in clinical settings [ 19 , 20 ]. In particular, cilostazol treatment is beneficial for a reduction in triglyceride levels and an increase in HDL-C levels in patients with PAD [ 19 , 25 ] or at high risk of cardiovascular disease (CVD) [ 20 ].…”

“…Recently, we and other researchers found that this compound has beneficial effects on metabolic parameters, angiogenesis, numbers and functions of circulating human early EPCs in vitro [ 18 , 21 – 24 ], in vivo [ 18 , 21 – 24 ], and in clinical settings [ 19 , 20 ]. In particular, cilostazol treatment is beneficial for a reduction in triglyceride levels and an increase in HDL-C levels in patients with PAD [ 19 , 25 ] or at high risk of cardiovascular disease (CVD) [ 20 ]. However, no study has investigated the effect of cilostazol on plasma PCSK9 levels.…”

“…In our study, we included participants from two double-blind, randomized, placebo-controlled trials [ 19 , 20 ] to evaluate the effect of cilostazol treatment on plasma PCSK9 levels and the potential mechanisms of action in patients with PAD or at high risk of CVD.…”

Biochemical and Biological Effects of Irisin in a Model of Diabetes Mellitus

“…Endothelial progenitor cells (EPCs) are responsible for the regeneration and repair of endothelium and their numbers and functions were found to be associated with cardiovascular complications caused by DM (Chao et al, 2016;Ye & Poh, 2015). Via the PI3K/AKT/eNOS pathways, irisin increased the number of EPCs in diabetic animals and improved their function.…”