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Cardiovascular Research Advance Access first published online on February 15, 2008
This version [Corrected Proof] published online on March 14, 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

Judith Sendra1, Vicenta Llorente-Cortés1, Paula Costales1, Claudia Huesca-Gómez1 and Lina Badimon1,2,*

1 Barcelona Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Av. S. Antoni M. Claret 167, 08025 Barcelona, Spain
2 CIBEROBN, Instituto Salud Carlos III, Barcelona, Spain

* Corresponding author. Tel: +34 935565880; fax: +34 935565559. E-mail address: lbadimon{at}csic-iccc.santpau.es

Aims: 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 two-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 normolipidaemic rat model, Ang II infusion produced a significant increase in aortic LRP1 expression and lipid infiltration in the arterial intima.

Conclusion: 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.

KEYWORDS Angiotensin II; Aggregated LDL; LRP1; AT1 receptors; Vascular smooth muscle cells; Arteriosclerosis

Time for primary review: 17 days


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