LDL
may cause
Atherosclerosis
LDL
may cause
Atherosclerosis
8.5
ValidityScore
Valid or Invalid?
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2009Publications Review
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Hansson GK -
«Abstract: Atherosclerosis, the cause of myocardial infarction, stroke and ischemic gangrene, is an inflammatory disease. When LDL accumulates in the intima, it activates the endothelium to express leukocyte adhesion molecules and chemokines that promote recruitment of monocytes and T cell. Monocyte-derived macrophage upregulate pattern recognition receptors, including scavenger receptors that mediate uptake of modified LDL, and Toll-like receptors, which transmit activating signals leading to release of cytokines, proteases, and vasoactive molecules. T cell in lesions recognize local antigens and mount Th1 responses with secretion of pro-inflammatory cytokines, thus contributing to local inflammation and growth of the plaque. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, and thrombus formation, triggering ischemia and infarction. Inflammatory markers are already used to monitor the disease process and anti-inflammatory therapy may be useful to control disease activity.»
- Organism: Humans
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#Atherosclerosis / pathology*, G K Hansson, Humans, Immune System / pathology, Inflammation / complications, Inflammation / etiology*, Inflammation / immunology, MEDLINE, NCBI, NIH, NLM, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, Non-U.S. Gov', PubMed Abstract, Research Support, Review, doi:10.1111/j.1538-7836.2009.03416.x, pmid:19630827, t -
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2008Rodents
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CHUN-LIN CHEN, JUNG SAN HUANG, SHUAN SHIAN HUANG -
«RESULTS: The TβR-II/TβR-I binding ratio of TGF-β has been shown to be positively correlated with TGF-β responsiveness in several cell systems (McCaffrey et al., 1995; Sankar et al., 1996; Coppa et al., 1997; McCaffrey et al., 1997; Letamendia et al., 1998; Eickelberg et al., 2002; Quan et al., 2004; Chen et al., 2006). We recently reported that the TβR-II/TβR-I binding ratio of TGF-β in TGF-β receptor oligomeric complexes on the cell surface is a signal determining TGF-β partitioning between lipid raft/caveolae- and clathrin-mediated endocytosis pathways and resultant TGF-β responsiveness (Huang and Huang, 2005; Chen et al., 2006). When the TβR-II/TβR-I binding ratio of TGF-β increases, more receptor-bound TGF-β (as Complex I, which contains more TβR-II than TβR-I and exists in non-lipid raft microdomains) undergoes clathrin-mediated endocytosis and generates signaling in endosomes, leading to promotion of TGF-β responsiveness; when the TβR-II/TβR-I binding ratio of TGF-β decreases, more receptor-bound TGF-β (as Complex II, which contains more TβR-I than TβR-II and exists in lipid rafts/caveolae) undergoes lipid raft/caveolae-mediated endocytosis and rapid degradation, resulting in suppression of TGF-β responsiveness (Chen et al., 2006). To determine if cholesterol treatment alters the TβR-II/TβR-I binding ratio of TGF-β, we first determined the time course of the effect of cholesterol treatment on the TβR-II/TβR-I binding ratio of 125I-TGF-β1 in Mv1Lu cell. These cell were treated with 50 μg/ml cholesterol at 37°C for several time periods. 125I-TGF-β1 binding to TβR-I and TβR-II was then determined by affinity labeling at 0°C using the bifunctional cross-linking agent DSS followed by 7.5% SDS–PAGE and autoradiography or quantification using a PhosphoImager. As shown in Figure 1, treatment of Mv1Lu cell with 50 μg/ml cholesterol increased binding of 125I-TGF-β1 to TβR-I in a time-dependent manner (Fig. 1A). The cholesterol-induced increase of 125I-TGF-β1 binding to TβR-I was observed within 10 min. Cholesterol increased 125I-TGF-β1 binding to TβR-I by –2-fold after a 60- or 120-min incubation, whereas it moderately affected 125I-TGF-β1 binding to TβR-II after the same time incubation (Fig. 1B). Cholesterol treatment for 60 or 120 min appeared to decrease the TβR-II/TβR-I binding ratio of 125I-TGF-β1 from 0.37 (in control cell treated without cholesterol) to 0.18 (Fig. 1C). These results indicate that cholesterol exerts its effect promptly.» Which in turn causes atherosclerosis.
- Organism: Mouse / Rat (Rodents)
- Comments: would amplify the effects on progression of atherosclerosis and other
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2007Publications Review
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Chun-Lin Chen, I-Hua Liu, Jung San Huang, Shuan Shian Huang, Steven J. Fliesler, Xianlin Han -
«RESULTS: Since cholesterol is an important structural component of lipid rafts and caveolae (Pike, 2003; Lee et al., 2004), the treatment of cell with cholesterol may suppress TGF-β-induced signaling, and thus TGF-β responsiveness by promoting formation of or stabilization of lipid rafts and caveolae. To test the effect of cholesterol on TGF-β-induced signaling, we determined the effect of cholesterol treatment on TGF-β-induced Smad2 phosphorylation and nuclear translocation, both of which are key signaling events, leading to TGF-β responsiveness (Heldin et al., 1997; Massague, 1998; Moustakas et al., 2001). Mink lung epithelial (Mv1Lu) cell, which are a standard model system for investigating TGF-β responsiveness, and bovine aorta endothelial cell (BAECs) were treated with increasing concentration of cholesterol at 37°C for 1 hour and then incubated with 50 pM TGF-β1 at 37°C for 30 minutes. P-Smad2 and Smad2 in the cell lysates were determined by 7.5% SDS-PAGE followed by western blot analysis using anti-P-Smad2 and anti-Smad2 antibodies and the enhanced chemiluminescence (ECL) system, and quantified by densitometry. As shown in Fig. 1A,B, cholesterol effectively suppressed Smad2 phosphorylation stimulated by TGF-β1 in a concentration-dependent manner in both Mv1Lu cell and BAECs. Cholesterol treatment appreciably suppressed Smad2 phosphorylation at concentration of 6-100 μg/ml. At 25 μg/ml, cholesterol suppressed Smad2 phosphorylation by ∼55% and ∼90% in Mv1Lu cell and BAECs, respectively. Cholesterol also suppressed Smad2 phosphorylation in a concentration-dependent manner in NRK cell. At 25 μg/ml, cholesterol suppressed Smad2 phosphorylation by ∼40% in these cell (data not shown). Since cholesterol is mainly present as lipoprotein complexes (e.g. LDL and VLDL) in plasma, we determined the effects of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) on Smad2 phosphorylation in Mv1Lu cell. As shown in Fig. 1C, LDL (50 μg protein/ml) treatment suppressed Smad2 phosphorylation by ∼60% in Mv1Lu cell and VLDL (5 μg/ml) slightly suppressed Smad2 phosphorylation in these cell. At 50 μg protein/ml, VLDL suppressed Smad2 phosphorylation by ∼55±5% (n=4) in Mv1Lu cell. The concentration (50 μg/ml) of LDL used in the experiment was chosen because it caused inhibition of Smad2 phosphorylation by ∼60%, which was similar to that induced by 25 μg/ml cholesterol (Fig. 1A). To determine the effect of cholesterol on Smad2 nuclear translocation, Mv1Lu cell were treated with 50 μg/ml cholesterol at 37°C for 1 hour and then further incubated with and without 50 pM TGF-β1 at 37°C for 30 minutes. These cell were subjected to immunofluorescent staining using anti-P-Smad2 antibody and nuclear 4′,6-diamidine-2-phenylindole (DAPI) staining. As shown in Fig. 1D, cholesterol suppressed Smad2 nuclear translocation (Fig. 1D,c versus b). Counting cell with Smad2 nuclear localization from four separate experiments indicated that TGF-β1 induced Smad2 nuclear translocation in all of the treated cell, whereas cholesterol suppressed Smad2 nuclear translocation in 60±5% of these cell. Taken together, these results suggest that cholesterol treatment suppresses TGF-β1-induced signaling.»
- Organism: Humans
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Comments:
This suggests that other factors such as continuous endothelial injury by high plasma LDL and/or cholesterol levels may facilitate
the progression of atherosclerosis in hypercholesterolemic animals
and that the combination of dietary TFs and hypercholesterolemia
would amplify the effects on progression of atherosclerosis and other
related diseases. -
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