Hypoxia Stimulates Low-Density Lipoprotein Receptor-Related Protein-1 Expression Through Hypoxia-Inducible Factor-1 alpha in Human Vascular Smooth Muscle Cells
Por:
Castellano, J, Aledo, R, Sendra, J, Costales, P, Juan-Babot, O, Badimon, L, Llorente-Cortes, V
Publicada:
1 jun 2011
Resumen:
Objective-Hypoxia is considered a key factor in the progression of atherosclerotic lesions. Low-density lipoprotein receptor-related protein (LRP1) plays a pivotal role in the vasculature. The aim of this study was 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 alpha).
Methods and Results-Real-time polymerase chain reaction and Western blot analysis demonstrated that hypoxia (1% O(2)) time-dependently induced LRP1 mRNA (maximum levels at 1 to 2 hours) and protein expression (maximum levels at 12 to 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 alpha overaccumulation induced LRP1 promoter activity and that 2 consensus hypoxia response element sites located at -1072/-1069 and -695/-692 participate in the induction. Chromatin immunoprecipitation showed the in vivo binding of HIF-1 alpha to LRP1 promoter in hypoxic VSMC. Hypoxia effects on LRP1 protein expression were functionally translated into an increased cholesteryl ester (CE) accumulation from aggregated low-density lipoprotein (agLDL) uptake. The blockade of HIF-1 alpha expression inhibited the upregulatory effect of hypoxia on LRP1 expression and agLDL-derived intracellular CE overaccumulation, suggesting that both LRP1 overexpression and CE overaccumulation in hypoxic vascular cells are dependent on HIF-1 alpha. Immunohistochemical analysis showed the colocalization of LRP1 and HIF-1 alpha in vascular cells of human advanced atherosclerotic plaques.
Conclusion-Hypoxia upregulates LRP1 expression and agLDL-derived intracellular CE accumulation in human VSMC through HIF-1 alpha induction. (Arterioscler Thromb Vasc Biol. 2011;31:1411-1420.)
Filiaciones:
Castellano, J:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Aledo, R:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Inst Salud Carlos III, CIBEROBN 06 03, Barcelona, Spain
Sendra, J:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Costales, P:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Juan-Babot, O:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Badimon, L:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
Inst Salud Carlos III, CIBEROBN 06 03, Barcelona, Spain
Llorente-Cortes, V:
Hosp Santa Creu & Sant Pau, Inst Catala Ciencies Cardiovasc, CSIC, Cardiovasc Res Ctr Barcelona, Barcelona 08025, Spain
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