当前位置： SCI文献检索 > JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY期刊下所有文献 > Carbamylated Low-Density Lipoproteins Induce a Prothrombotic State Via LOX-1: Impact on Arterial Thrombus Formation In Vivo.

Carbamylated Low-Density Lipoproteins Induce a Prothrombotic State Via LOX-1: Impact on Arterial Thrombus Formation In Vivo.

Abstract：

BACKGROUND:Carbamylation alters low-density lipoprotein (LDL) structure and is thought to promote vascular inflammation and dysfunction in patients with chronic kidney disease (CKD). OBJECTIVES:This study sought to determine whether carbamylated LDL (cLDL) exerts prothrombotic effects in vascular cells and platelets and whether cLDL enhances arterial thrombus formation in vivo. METHODS:LDL was isolated from healthy subjects or patients with CKD by sequential ultracentrifugation. Ex vivo carbamylation of LDL from healthy subjects was induced with potassium cyanate. Arterial thrombus formation was analyzed in a murine carotid artery photochemical injury model. Protein expression and mRNA levels were analyzed by Western blotting, flow cytometry, and real-time PCR. Platelet aggregation was measured by impedance aggregometry. RESULTS:Intravenous administration of cLDL in mice accelerated arterial thrombus formation compared to treatment with native LDL (nLDL) or vehicle. Tissue lysates of mouse carotid arteries revealed that cLDL induced the expression of TF, PAI-1, and LOX-1 mRNA in vascular cells. In human aortic smooth muscle and endothelial cells, cLDL induced TF and PAI-1 expression. In contrast, nLDL had no effect on either cell type. While nLDL and cLDL had no aggregatory effect on resting platelets, cLDL enhanced platelet aggregation in response to different agonists. This effect was mediated by mitogen-activated protein kinase p38 phosphorylation and LOX-1 translocation to the surface. LDL isolated from patients with CKD mimicked the prothrombotic effects of cLDL on vascular cells, platelets, and thrombus formation in vivo. CONCLUSIONS:We found that cLDL induces prothrombotic effects in vascular cells and platelets by activation of the LOX-1 receptor and enhances thrombus formation in vivo. This observation reveals a new mechanism underlying the increased incidence of acute thrombotic events observed in patients with CKD and may lead to the development of new lipid-targeting therapies in this population.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Holy EW,Akhmedov A,Speer T,Camici GG,Zewinger S,Bonetti N,Beer JH,Lüscher TF,Tanner FC

doi

10.1016/j.jacc.2016.07.755

subject

Has Abstract

pub_date

2016-10-11 00:00:00

pages

1664-1676

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(16)34924-5

journal_volume

pub_type

杂志文章

在线工具

Carbamylated Low-Density Lipoproteins Induce a Prothrombotic State Via LOX-1: Impact on Arterial Thrombus Formation In Vivo.