Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse.

Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Circulation Research (Impact Factor: 11.86). 04/2007; 100(5):670-7. DOI: 10.1161/01.RES.0000260204.40510.aa
Source: PubMed

ABSTRACT Macrophage low-density lipoprotein receptor-related protein (LRP) mediates internalization of remnant lipoproteins, and it is generally thought that blocking lipoprotein internalization will reduce foam cell formation and atherogenesis. Therefore, our study examined the function of macrophage LRP in atherogenesis. We generated transgenic mice that specifically lack macrophage LRP through Cre/lox recombination. Transplantation of macrophage LRP(-/-) bone marrow into lethally irradiated female LDLR(-/-) recipient mice resulted in a 40% increase in atherosclerosis. The difference in atherosclerosis was not caused by altered serum lipoprotein levels. Furthermore, deletion of macrophage LRP decreased uptake of (125)I-very-low-density lipoprotein compared with wild-type cells in vitro. The increase in atherosclerosis was accompanied by increases in monocyte chemoattractant protein type-1, tumor necrosis factor-alpha, and proximal aorta macrophage cellularity. We also found that deletion of macrophage LRP increases matrix metalloproteinase-9. This increase in matrix metalloproteinase-9 was associated with a higher frequency of breaks in the elastic lamina. Contrary to what was found with other lipoprotein receptors, deletion of LRP increases atherogenesis in hypercholesterolemic mice. Our data support the hypothesis that macrophage LRP modulates atherogenesis through regulation of inflammatory responses.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies related to the functional and regulatory aspects of proteolytic processing are of interest to cell biologists, developmental biologists and investigators who work on human diseases. Much of what is known about this topic derives from the study of the proteolytic processing of the amyloid precursor protein (APP), which is involved in the pathology of Alzheimer’s disease, and of the Notch protein and its Delta ligand, which play roles during embryonic development and in biologic processes in the adult. The proteolytic processing of plasma membrane receptor proteins is under the control of different enzymes that are responsible for releasing the ectodomain into the extracellular environment, where it has the potential to function as a signaling molecule and/or regulate the availability of the receptor’s ligand. Following shedding of the ectodomain, the γ-secretase enzymatic complex cleaves the transmembrane domain and releases the cytoplasmic domain (ICD) of the receptor. The ICD can function in the cytoplasm and/or at the nucleus. Members of the low-density lipoprotein receptor (LDLR) family are endocytic-signaling proteins that perform a wide variety of physiologic functions during development and in the adult life. In addition these receptors have been implicated in a variety of diseases in adults. The prototypic receptor for this family of proteins is the LDLR itself. Besides their binding to apolipoproteins, these receptors bind many ligands that are destined for internalization and degradation. Some ligands have signaling properties. The proteolytic processing of certain members of the LDLR family not only controls receptor availability at the cell surface but also has functional consequences that amplify the spectrum of roles that these receptors perform. In addition, many complex regulatory mechanisms control the proteolytic processing of these receptors.
    Frontiers in biology. 10/2011; 7(2):113–143.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this thesis we aimed to expand our knowledge on the pathophysiological aspects of the metabolic syndrome in transgenic mice. The metabolic syndrome involves multiple aspects and has a major impact on cardiovascular diseases. In the first part of thesis the role of PAI-1 in the development of insulin resistance will addressed. This part will also focus on the mechanism of plasma PAI-1 clearance. In the second part of this thesis, the roles of LRP in atherosclerosis and LPL activity in lipid metabolism are addressed. In this thesis we showed the PAI-1 catabolism is facilitated by a RAP-sensitive mechanism other than LRP, LDLR and VLDLR. The increased plasma PAI-1 levels observed in insulin resistance and obesity is not explained by impaired clearance of PAI-1. The increased plasma PAI-1 levels might be an epiphenomenon of the chronic inflammatory state of insulin resistance or obesity. Furthermore, alternative pathways other than the traditional lipoprotein receptors are involved in the regulation of plasma cholesterol and triglyceride levels. The development of atherosclerosis is multi-factorial in which the balance between the antiand pro-inflammatory processes plays a central role. Macrophage LRP might be one of the features that control this balance. Inflammation not only promotes to the development of atherosclerosis, but might also be involved in the processes that restore the damaged vascular wall.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sterol regulatory element-binding proteins (SREBPs) negatively modulate the expression of the CD91/low-density lipoprotein receptor-related protein (LRP1), a carrier and signaling receptor that mediates the endocytosis of more than 40 structurally and functionally distinct ligands. The aim of this work was to analyze whether lipopolysaccharide (LPS) can regulate LRP1 expression through SREBPs in human monocyte-derived macrophages (HMDM). LPS led to LRP1 mRNA and protein inhibition in a dose- and time-dependent manner. Concomitantly, a strong upregulation of SREBP-1 mRNA and SREBP-1 nuclear protein levels was observed in LPS-treated HMDM. The specific silencing of SREBP-1 efficiently prevented LRP1 reduction caused by LPS. SREBP-1 mRNA and nuclear protein levels remained high in HMDM treated with LPS unexposed or exposed to LDL. Native (nLDL) or aggregated LDL (agLDL) per se downregulated SREBP-2 expression levels and increased LRP1 expression. However, lipoproteins did not significantly alter the effect of LPS on SREBP-1 and LRP1 expression. Collectively, these data support that lipoproteins and LPS exert their modulatory effect on LRP1 expression through different SREBP isoforms, SREBP-2 and SREBP-1, respectively. These results highlight a crucial role of SREBP-1 as a mediator of the downregulatory effects of LPS on LRP1 expression in human macrophages, independently of the absence or presence of modified lipoproteins.
    Atherosclerosis 12/2012; · 3.71 Impact Factor