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

I-Chih Chen,Ping-Yen Liu,Yi-Heng Li,Ting-Hsing Chao,Wei-Kung Tseng,Shih-Ya Tseng

doi:10.18632/oncotarget.22448

Abstract

The protein complex proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important target for the prevention and treatment of atherosclerosis and lipid homeostasis. This study investigated the effect of cilostazol on plasma PCSK9 concentrations. We performed a post hoc analysis of two prospective, double-blind, randomized controlled trials including 115 patients of whom 61 received cilostazol 200 mg/day and 54 received placebo for 12 weeks. Linear regression analysis was performed to determine the associations between several parameters and changes in PCSK9 levels. Use of cilostazol, but not placebo, significantly increased plasma PCSK9 concentrations, high-density lipoprotein cholesterol levels, and number of circulating endothelial progenitor cells (EPCs), and decreased triglyceride levels with a trend toward an increase in total cholesterol (TC) levels. A reduction in hemoglobin A1C and an increase in plasma vascular endothelial growth factor and adiponectin levels with cilostazol treatment were also found. Changes in the number of circulating EPCs were positively correlated and the TC concentrations were inversely correlated with changes in the PCSK9 levels. After adjusting for changes in levels of TC and numbers of circulating EPCs and history of metabolic syndrome, use of cilostazol remained independently associated with changes in plasma PCSK9 levels. In conclusion, cilostazol treatment was significantly and independently associated with an increase in plasma PCSK9 levels in patients with peripheral artery disease or at a high risk of cardiovascular disease regardless of background statin use and caused an improvement in some metabolic disorders and levels of vasculo-angiogenic biomarkers.

Highlights

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays an important role in cholesterol homeostasis and affects plasma lipoprotein levels by enhancing the degradation of hepatic low-density lipoprotein receptors and subsequently reducing expression of these receptors on hepatocytes, thereby leading to increased plasma levels of total cholesterol (TC) and low-density lipoprotein cholesterol www.impactjournals.com/oncotarget (LDL-C) [1]
We found that circulating endothelial progenitor cell (EPC) dysfunction, in particular, the number of apoptotic circulating endothelial cells, and some vasculo-angiogenic and oxidative biomarkers were significantly correlated with proprotein convertase subtilisin/kexin type 9 (PCSK9) levels [11]
By evaluating two prospective, randomized, doubleblinded, placebo-controlled trials in the current post hoc analysis, we found, for the first time, that cilostazol treatment was significantly and independently associated with an increase in plasma PCSK9 levels in patients with peripheral artery disease (PAD) or at a high risk of cardiovascular disease (CVD) regardless of background statin use

Summary

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays an important role in cholesterol homeostasis and affects plasma lipoprotein levels by enhancing the degradation of hepatic low-density lipoprotein receptors and subsequently reducing expression of these receptors on hepatocytes, thereby leading to increased plasma levels of total cholesterol (TC) and low-density lipoprotein cholesterol www.impactjournals.com/oncotarget (LDL-C) [1]. From a genetic point of view, individuals with certain sequence variations in the PCSK9 gene have lower plasma LCL-C levels and a lower incidence of coronary artery disease (CAD) [2]. Plasma PCSK9 levels are correlated with atherogenic lipoprotein levels and with many other cardiovascular risk factors, such as fasting plasma glucose, age, and blood pressure [3, 4]. Plasma PCSK9 levels have been reported to be associated with the severity of CAD [10], and the presence of peripheral artery disease (PAD), especially those with extensive, severe, and complicated PAD [11]. We found that circulating endothelial progenitor cell (EPC) dysfunction, in particular, the number of apoptotic circulating endothelial cells, and some vasculo-angiogenic and oxidative biomarkers were significantly correlated with PCSK9 levels [11]. PCSK9 protein is an important target for the prevention and treatment of atherosclerosis

Methods

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Conclusion