• 作者：José ; Castellano^a ; Rosa Aledo^a ; Judith Sendra^a ; Paula Costales^a ; Lina Badimon^a ; ^b ; Vicenta Llorente-Corté ; s^a ; ^{cllorente@csic-iccc.org} ;
• 关键词：Aterosclerosis ; Hipoxia ; Cé ; lulas vasculares ; Low density lipoprotein receptor-related protein-1 (LRP1) ; Hypoxia-inducible factor-1伪 (HIF-1伪)
• 刊名：Cl篓陋nica e Investigaci篓庐n en Arteriosclerosis
• 出版年：2012
• 期刊代码：pca88_02149168
• 类别：med
• 出版时间：May-June, 2012
• 卷：24
• 期：3
• 页码：115-130
• 文件大小：1518 K

Objective

Hypoxia is considered a key factor in the progression of atherosclerotic lesions. Low density lipoprotein receptor-related protein 1 (LRP1) plays a pivotal role in the vasculature. The aims of this study were to investigate the effect of hypoxia on LRP1 expression and function in vascular smooth muscle cells (VSMC) and the role of hypoxia-inducible factor alpha (HIF-1伪).

Methods and results

Real time PCR and Western blot analysis demonstrated that hypoxia (1%O₂) time-dependently induced LRP1 mRNA (maximum levels at 1-2 hours) and protein expression (maximum levels at 12-24 hours). The delayed hypoxic upregulation of LRP1 protein versus mRNA may be explained by the long half-life of LRP1 protein. Luciferase assays demonstrated that hypoxia and HIF-1伪 over-accumulation induced LRP1 promoter activity and that two consensus HRE sites located at -1072/-1069 and -695/-692 participate in the induction. Chromatin immunoprecipitation showed the in vivo binding of HIF-1伪 to LRP1 promoter in hypoxic VSMC. Hypoxia effects on LRP1 protein expression were functionally translated into an increased cholesteryl ester (CE) accumulation from aggregated LDL (agLDL) uptake. The blockade of HIF-1伪 expression inhibited the upregulatory effect of hypoxia on LRP1 expression and agLDL-derived intracellular CE over-accumulation, suggesting that both LRP1 overexpression and CE over-accumulation in hypoxic vascular cells are dependent on HIF-1伪. Immunohistochemical analysis showed the colocalization of LRP1 and HIF-1伪 in vascular cells of human advanced atherosclerotic plaques.

Conclusions

Hypoxia upregulates LRP1 expression and agLDL-derived intracellular CE accumulation in human VSMC through HIF-1伪 induction.