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


RESULTS
Here, we report for the first time that Ang II induces the upregulation of LRP1 expression in VSMC. Ang II (1 microM) 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 microg/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.


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.
Sendra
Judith
J
Barcelona Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Av. S. Antoni M. Claret 167, 08025 Barcelona, Spain.
Llorente-Cortés
Vicenta
V
Costales
Paula
P
Huesca-Gómez
Claudia
C
Badimon
Lina
L
D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007781:Lactoferrin / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D002788:Cholesterol Esters; D007093:Imidazoles; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C073402:PD 123319; D007781:Lactoferrin; D019808:Losartan