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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 15, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn043
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Angiotensin II upregulates LDL receptor-related protein (LRP1) expression in the vascular wall. A new pro-atherogenic mechanism of hypertension

J Sendra1, V Llorente-Cortés1, P Costales1, C Huesca-Gómez1 and L Badimon1,2

1 Barcelona Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau Barcelona, Spain
2 CIBEROBN, Instituto Salud Carlos III Barcelona, Spain

Address correspondence to: Prof. Lina Badimon, Cardiovascular Research Center,CSIC-ICCC, Hospital de la Santa Creu I Sant Pau Sant Antoni Ma Claret, 167 08025 Barcelona Tel: 0034-935565880; FAX: 0034-935565559; E-mail: lbadimon{at}csic-iccc.santpau.es

Aim: Hypertension is a risk factor for atherothrombotic vascular events. Angiotensin II (Ang II), one of the main vasoactive hormones of the renin-angiotensin system, has been associated with the development and progression of atherosclerosis. However, it is not fully known how Ang II contributes to lipid-enriched atherosclerotic lesion formation. In human vascular smooth muscle cells (VSMC), low density lipoprotein (LDL) receptor-related protein (LRP1) internalizes cholesteryl esters (CE) from extracellular matrix-bound aggregated LDL (agLDL). The aim of this study was to investigate the effect of Ang II on LRP1 expression and function in VSMC.

Methods and Results: Here, we report for the first time that Ang II induces the upregulation of LRP1 expression in VSMC. Ang II (1 µM) induced maximal LRP1 mRNA expression at 12 h and maximal protein overexpression (by 4.10-fold) at 24 h in cultured human VSMC. Ang II effects were functionally translated into an increased CE accumulation from agLDL uptake (by 2-fold at 50 µg/mL) that was prevented by the LRP1 ligand lactoferrin and by siRNA-LRP1 treatment. Ang II-LRP1 upregulation and excess CE accumulation from agLDL were prevented by losartan (an AT1 blocker) but not by PD123319 (a specific AT2 blocker). Additionally, in a normolipidemic rat model, Ang II infusion produced a significant increase in aortic LRP1 expression and lipid infiltration in the arterial intima.

Conclusions: The in vitro and in vivo data reported here indicate that Ang II upregulates LRP1 receptor expression and LRP1-mediated aggregated LDL uptake in vascular cells.

Time for primary review: 17 days


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