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

Sendra, Judith; Llorente‐Cortés, Vicenta; Costales, Paula; Huesca-Gómez, Claudia; Badimon, Lina

doi:10.1093/cvr/cvn043

Cited by 43 publications

(29 citation statements)

References 33 publications

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“…In agreement with previous studies [11,14], we showed that LRP1 is overexpressed in human lipid-enriched advanced coronary atherosclerotic plaques [13]. In a model of angiotensin II-infused rats, we found a significant and positive correlation between LRP1 mRNA expression and systolic blood pressure in both thoracic and abdominal aortas [15]. Finally, in type 2 diabetic patients with clinical stage IV of peripheral arterial occlusive disease, we reported the overexpression of LRP1 in occluded popliteal artery with atherosclerotic plaque compared to femoral veins [16].…”

Section: Introductionsupporting

confidence: 92%

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Gonzalo-Calvo¹,

Cenarro

Martínez-Bujidos

et al. 2015

International Journal of Cardiology

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Section: Introductionsupporting

confidence: 92%

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Gonzalo-Calvo¹,

Cenarro

Martínez-Bujidos

et al. 2015

International Journal of Cardiology

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“…14,15 However, neither AngII nor agLDL further increased hypoxia-induced LRP1 in hVSMCs. pPyk2/total Pyk2 ratio was induced by AngII ( Figure 5A) but not by agLDL ( Figure 5C).…”

Section: Response Of Hvsmcs To Hypoxia In the Presence Of Extracellulmentioning

confidence: 94%

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Revuelta‐López

Castellano

Roura

et al. 2013

ATVB

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Objective— Hypoxia disturbs vascular function by promoting extracellular matrix remodeling. Extracellular matrix integrity and composition are modulated by metalloproteinases (MMPs). Our aim was to investigate the role of low-density lipoprotein receptor–related protein 1 (LRP1) in regulating MMP-9/MMP-2 activation and vascular smooth muscle cells (VSMCs) migration in response to hypoxia, and to elucidate the LRP1-signaling pathways involved in this process. Approach and Results— Western blot analysis showed that hypoxia induced a sustained phosphorylation of proline-rich tyrosine kinase 2 concomitantly with LRP1 overexpression in human VSMCs (hVSMCs). Deletion of LRP1 using small-interfering RNA technology or treatment of hVSMCs with the Src family kinase inhibitor PP2 impaired hypoxia-induced phosphorylation of proline-rich tyrosine kinase 2 levels. Coimmunoprecipitation experiments showed that the higher amounts of phosphorylation of proline-rich tyrosine kinase 2/LRP1β immunoprecipitates in hypoxic hVSMCs were abolished in PP2-treated hVSMCs. Both LRP1 silencing and PP2 treatment were highly effective in the prevention of hypoxia-induced MMP-9 activation and hVSMC migration. Cellular subfractionation experiments revealed that PP2 effects may be caused by impairment of hypoxia-induced nuclear factor-κβ translocation to the nucleus. ELISA measurements showed that LRP1 silencing but not PP2 treatment increased interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 secretion by hypoxic hVSMCs. Conclusions— Our findings determine a crucial role of LRP1-mediated Pyk2 phosphorylation on hypoxia-induced MMP-9 activation and hVSMC migration and therefore in hypoxia-induced vascular remodeling. Both LRP1 silencing and PP2 treatments also influence hypoxia-induced proinflammatory effects in hVSMCs. Therefore, further studies are required to establish therapeutical strategies that efficiently modulate vascular remodeling and inflammation associated with hypoxia-vascular diseases.

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“…LRP1-mediated agLDL internalization is one of the main mechanisms contributing to VSMC-foam cell formation in experimental hyperlipidemia and hypertension. [22][23][24]26,27 Interestingly, foam cells colocalize with HIF-1␣ protein in the lipidic areas of human advanced atherosclerotic lesions. 3,4 Foam cells derive not only from macrophages but also from VSMC.…”

mentioning

confidence: 99%

“…25 Lowdensity lipoprotein receptor-related protein 1 (LRP1), the lipoprotein receptor that binds and internalizes agLDL, 23,24 is upregulated by hypercholesterolemia 26 and hypertension. 27 LDL stimulates LRP1 transcription through the downregulation of sterol regulatory element binding protein (SREBP). 26 SREBP-1 and SREBP-2 transcription factors negatively modulate LRP1 transcription in human VSMC.…”

mentioning

confidence: 99%

Hypoxia Stimulates Low-Density Lipoprotein Receptor–Related Protein-1 Expression Through Hypoxia-Inducible Factor-1α in Human Vascular Smooth Muscle Cells

Castellano

Aledo

Sendra

et al. 2011

ATVB

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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-␣ (HIF-1␣). 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␣ overaccumulation induced LRP1 promoter activity and that 2 consensus hypoxia response element sites located at Ϫ1072/Ϫ1069 and Ϫ695/Ϫ692 participate in the induction. Chromatin immunoprecipitation showed the in vivo binding of HIF-1␣ 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␣ 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␣. Immunohistochemical analysis showed the colocalization of LRP1 and HIF-1␣ in vascular cells of human advanced atherosclerotic plaques. H ypoxia plays a pivotal role in the pathophysiology of cancer, myocardial infarction, and atherosclerosis. Arterial wall thickness associated with atherosclerotic plaque progression reduces the oxygen supply in certain areas of the vascular intima. 1,2 Hypoxia is present in human advanced atherosclerotic lesions and correlates with the presence of angiogenesis and thrombus. 3,4 Most of the cells in hypoxic areas of atherosclerotic plaques respond by altering the expression of genes involved in vasculogenesis, angiogenesis, inflammation, and lipid deposition. [5][6][7][8][9][10][11] These genes are activated through hypoxia-inducible factor-1 complex (HIF-1). The HIF-1␣ subunit is subjected to quick oxygendependent proteasomal degradation through hydroxylation of proline residues by hydroxylases. [12][13][14] Under low oxygen tensions, HIF-1␣ accumulates and heterodimerizes with the constitutively expressed beta subunit, allowing the HIF-1 complex to bind to hypoxia response element (HRE) sequences in target promoters. 15 It has been reported that HIF-1␣ accumulation in macrophages promotes foam cell formation and atherosclerosis. 16 In experimental models of hypercholesterolemia and hypertension, HIF-1␣ is also associated with vascular smooth muscle cells (VSMC). 17 30 -32 It is unknown whether hypoxia may modulate LRP1 expression in human atherosclerotic plaques and, if so, which transcription ...

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

Abstract: 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.

Cited by 43 publications

References 33 publications

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Hypoxia Stimulates Low-Density Lipoprotein Receptor–Related Protein-1 Expression Through Hypoxia-Inducible Factor-1α in Human Vascular Smooth Muscle Cells

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