La aportación de la vanguardia artística soviética a la exposición teatral de Viena.
1.3.4. LA ESCENA CONSTRUCTIVISTA Las construcciones de Popova y Vesnín para Meyerhold y Taíro
enhances atherosclerosis
in ApoE/LDLR double knockout mice.
L. Hu1, L.S.M. Boesten2, P. May3, J. Herz4, N. Bovenschen5, M.V. Huisman1, J.F.P. Berbée1, L.M. Havekes1,2, B.J.M. van Vlijmen6, J.T. Tamsma1
1Departments of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands 2TNO Quality of Life, Gaubius Laboratory, Leiden, The Netherlands 3Zentrum für Neurowissenschaften/Medizinische Klinik II, Universität Freiburg, Freiburg, Germany 4Department. of Molecular Genetics, UT Southwestern, Dallas, USA 5Department of Pathology, University Medical Center Utrecht, Utrecht 6Department of Haemostasis and Thrombosis, Leiden University Medical Center, Leiden, The Netherlands 6Human Genetics, Leiden University Medical Center, Leiden,
The Netherlands Arterioscler Thromb Vasc Biol (2006) 26:2710-5
C ha pa te r 5 76 76
Abstract
Objective – In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins.
Methods and Results – We generated macrophage specific LRP deficient mice on an ApoE/ LDLR double deficient background. Macrophage LRP deletion did not affect plasma choles- terol and triglyceride levels, lipoprotein distribution, and blood monocyte counts. Never- theless, macrophage LRP deficiency resulted in a 1.8-fold increase in total atherosclerotic lesion area in the aortic root of 18-week old mice. Moreover, LRP deficiency also resulted in a relatively higher number of advanced lesions. Whereas macrophage and smooth muscle cell content did not differ between LRP deficient mice and control littermates, a 1.7-fold increase in collagen content and 2.3-fold decrease in relative number of CD3+ T cells were observed in lesions from macrophage specific LRP deficient mice.
Conclusions – Our data demonstrate that, independent of its role in lipoprotein uptake, absence of LRP in macrophages resulted in more advanced atherosclerosis and in lesions that contained more collagen and less CD3+ T cells. In contrast to previous in vitro studies, we conclude that macrophage LRP has an atheroprotective potential and may modulate the extracellular matrix in the atherosclerotic lesions.
Introduction
Cardiovascular diseases are the leading cause of morbidity and mortality in the Western World. The primary cause of cardiovascular diseases is atherosclerosis, which is characterised by lipid accumulation and inflammation in the vascular wall.1,2 Macrophages play a central role in the pathogenesis of atherosclerosis by internalising modified low-density lipoprotein (LDL), production of cytokines and growth factors, and thus stimulate migration and proliferation of smooth muscle cells (SMCs), and plaque development and progression.1
The LDL receptor (LDLR)-related protein (LRP) is a large cell-surface multi-ligand endocytic clearance and signalling receptor of the LDLR gene family.3-8 LRP is known to recognise >50 structurally and functionally different ligands.9,10 It is expressed in a variety of cell types including hepatocytes, SMCs, and macrophages.11 The hepatic LRP was originally identified as an endocytic receptor for apolipoprotein E (apoE)-rich lipoproteins.4 Recently, we showed that hepatic LRP deficiency in mice increased atherosclerosis independent of plasma lipo- proteins.12 Similarly, SMC specific LRP deficient mice display impaired vessel wall integrity and have increased susceptibility to cholesterol-diet induced atherosclerosis.7 These data show that LRP protects against the development of atherosclerosis at the level of the liver and the SMC, independent of its role in the removal of plasma lipoproteins.
In contrast, several lines of in vitro evidence show that LRP in macrophages has pro-athero- genic properties. First, LRP is highly expressed in atherosclerotic lesions and upregulated in macrophages undergoing foam cell formation.13,14 Second, LRP regulates β2-integrin- mediated adhesion of monocytes to endothelial cells,15 allowing monocytes to migrate into the intima and to differentiate into macrophages. Third, macrophage LRP has also been demonstrated to play a role in the translocation of 12/15-lipoxygenase, which stimulates the formation of oxidised LDL.16,17 Finally, in concert with the LDLR, LRP can mediate the uptake of apoE-rich atherogenic lipoproteins into the macrophage.18-20 Because all these processes promote the formation of foam cells, one would predict that LRP promotes the development of atherosclerosis at the level of macrophages.
In the present study, we investigated the role of macrophage LRP in the development of atherosclerosis in vivo. To this end,macrophage LRP was constitutively deleted in macro- phages, using the lysozyme M Cre/loxP system.21 Because apoE LDLR double deficient mice develop spontaneously human-like atherosclerosis without the necessity of a cholesterol- rich diet, macrophage LRP was deleted on an apoE22 and LDLR23 double deficient back- ground. Moreover, this model allowed us to study the role of macrophage LRP independent of its classical role in the uptake of lipoproteins via the apoE- and LDLR-mediated path- way. Our data demonstrate that the absence of macrophage LRP results in more advanced atherosclerosis, and in lesions that contain more collagen and less CD3+ T cells. In contrast to what in vitro studies would predict, we conclude that, like LRP on hepatocytes and SMCs, macrophage LRP has an atheroprotective potential.
C ha pa te r 5 78 78