Diabetic HDL Is Dysfunctional in Stimulating Endothelial Cell Migration and Proliferation Due to Down Regulation of SR-BI Expression

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.

Administration of high dose eicosapentaenoic acid enhances anti-inflammatory properties of high-density lipoprotein in Japanese patients with dyslipidemia

“…It has been demonstrated that normal HDL has the capability to promote endothelial cell proliferation and migration [20], whereas HDL from CAD patients loses the capacity of endothelial repair compared to normal HDL [21]. The present study proved that the HDL after EPA treatment markedly promoted the endothelial repair compared to that before EPA treatment (155.0 ± 10.9 vs. 201.5 ± 11.6%, p < 0.05, Fig.…”

“…Previous studies reported that endothelial cell migration is closely related to scavenger receptor class B, type 1 (SR-B1) on the endothelial cell. Moreover, HDL modifications such as oxidation can down-regulate SR-B1 expression and Akt activity, and then SR-B1-mediated activation of Rac GTPase in the endothelial cell [20]. In contrast, n-3 PUFA treatment up-regulates apo A-1 [33], which stabilizes PON1 and stimulate endothelial SR-B1.…”

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

“…HDL from patients with type 2 diabetes has recently been found to have a diminished capacity to stimulate endothelial cell proliferation, migration, and adhesion to the extracellular matrix, and this impairment is associated with downregulation of SR-BI expression ( 174 ). Notably, we have observed that HDL from patients with CAD has impaired endothelial repair capacity following vascular injury in vivo using the nude mouse carotid artery injury model ( 15 ).…”

Myeloperoxidase-oxidized high density lipoprotein impairs atherosclerotic plaque stability by inhibiting smooth muscle cell migration

“…SR-BI (scavenger receptor BI) −/− mice (C57BL/6 background) were obtained from Dr. George Liu’s laboratory (Peking University, Beijing, China) [27]. Eight-week-old male ApoE−/− mice were purchsed from Charles River Laboratories (Wilmington, Massachusetts).…”