Diabetic HDL is dysfunctional in stimulating endothelial cell migration and proliferation due to down regulation of SR-BI expression.

Bing Pan,Bing Pan,Baoqi Yu,George Liu,George Liu,Lemin Zheng,Lemin Zheng,Liang Ji,Liang Ji,Yijing Ma,Hui Ren,Hui Ren,Xiaofeng Lv,Yuhui Wang,Yuhui Wang,Yubin He,Yijing Ma,Yongyu Wang,Yongyu Wang,Subramaniam Pennathur,Subramaniam Pennathur,Baoqi Yu,Donghui Liu,Donghui Liu,Y Eugene Chen,Y Eugene Chen,Jonathan D Smith,Michael E Boulton

doi:10.1371/journal.pone.0048530

Abstract

BackgroundDiabetic HDL had diminished capacity to stimulate endothelial cell (EC) proliferation, migration, and adhesion to extracellular matrix. The mechanism of such dysfunction is poorly understood and we therefore sought to determine the mechanistic features of diabetic HDL dysfunction.Methodology/Principal FindingsWe found that the dysfunction of diabetic HDL on human umbilical vein endothelial cells (HUVECs) was associated with the down regulation of the HDL receptor protein, SR-BI. Akt-phosphorylation in HUVECs was induced in a biphasic manner by normal HDL. While diabetic HDL induced Akt phosphorylation normally after 20 minutes, the phosphorylation observed 24 hours after diabetic HDL treatment was reduced. To determine the role of SR-BI down regulation on diminished EC responses of diabetic HDL, Mouse aortic endothelial cells (MAECs) were isolated from wild type and SR-BI (−/−) mice, and treated with normal and diabetic HDL. The proliferative and migratory effects of normal HDL on wild type MAECs were greatly diminished in SR-BI (−/−) cells. In contrast, response to diabetic HDL was impaired in both types suggesting diminished effectiveness of diabetic HDL on EC proliferation and migration might be due to the down regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically.Conclusions/SignificanceDiabetic HDL was dysfunctional in promoting EC proliferation, migration, and adhesion to matrix which was associated with the down-regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically.

Highlights

Lipid metabolism disorders associated with type 2 diabetes, such as increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL), have been linked to multiple biological processes implicated in the development of atherosclerosis [1]
While N-HDL led to increased cell number, D-HDL has 18% less effect compared to N-HDL (Fig. 1A, n = 6, p,0.001 comparing N-HDL vs. D-HDL)
24hour treatment with D-HDL resulted in significant downregulation in scavenger receptor class B type I (SR-BI) expression on human umbilical vein endothelial cells (HUVECs) surface compared with N-HDL or no treatment (Control) (Fig. 4F)

Summary

Introduction

Lipid metabolism disorders associated with type 2 diabetes, such as increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL), have been linked to multiple biological processes implicated in the development of atherosclerosis [1]. HDL has multiple endothelial actions that afford cardiovascular protection, including antioxidant, anti-inflammatory, anti-apoptotic, and anti-thrombotic activities [4]. HDL activates endothelial nitric oxide synthase [5], enhances endothelial progenitor cell (EPC) mediated endothelium repair, and stimulates EC proliferation and migration [6]. Diabetic HDL had diminished capacity to stimulate endothelial cell (EC) proliferation, migration, and adhesion to extracellular matrix. The mechanism of such dysfunction is poorly understood and we sought to determine the mechanistic features of diabetic HDL dysfunction

Methods

Results

Conclusion