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• W2037641639 abstract "Angiotensin II (angII) is known to promote atherosclerosis; however, the mechanisms involved are not fully understood. To determine whether angII stimulates proteoglycan production and LDL retention, LDL receptor-deficient mice were infused with angII (1,000 ng/kg/min) or saline via osmotic minipumps. To control for the hypertensive effect of angII, a parallel group received norepinephrine (NE; 5.6 mg/kg/day). Arterial lipid accumulation was evaluated by measuring the retention rate of LDL in isolated carotid arteries perfused ex vivo. Mice infused with angII had increased vascular content of biglycan and perlecan and retained twice as much LDL as saline- or NE-infused mice, although no group developed atherosclerosis at this time. To determine whether this increase in biglycan and perlecan content predisposed to atherosclerosis development, mice were infused with angII, saline, or NE for 4 weeks, then pumps were removed and mice received an atherogenic Western diet for another 6 weeks. Mice that had received angII infusions had 3-fold increased atherosclerosis compared with mice that had received saline or NE, and apolipoprotein B colocalized with both proteoglycans. Thus, one mechanism by which angII promotes atherosclerosis is increased proteoglycan synthesis and increased arterial LDL retention, which precedes and contributes to atherosclerosis development. Angiotensin II (angII) is known to promote atherosclerosis; however, the mechanisms involved are not fully understood. To determine whether angII stimulates proteoglycan production and LDL retention, LDL receptor-deficient mice were infused with angII (1,000 ng/kg/min) or saline via osmotic minipumps. To control for the hypertensive effect of angII, a parallel group received norepinephrine (NE; 5.6 mg/kg/day). Arterial lipid accumulation was evaluated by measuring the retention rate of LDL in isolated carotid arteries perfused ex vivo. Mice infused with angII had increased vascular content of biglycan and perlecan and retained twice as much LDL as saline- or NE-infused mice, although no group developed atherosclerosis at this time. To determine whether this increase in biglycan and perlecan content predisposed to atherosclerosis development, mice were infused with angII, saline, or NE for 4 weeks, then pumps were removed and mice received an atherogenic Western diet for another 6 weeks. Mice that had received angII infusions had 3-fold increased atherosclerosis compared with mice that had received saline or NE, and apolipoprotein B colocalized with both proteoglycans. Thus, one mechanism by which angII promotes atherosclerosis is increased proteoglycan synthesis and increased arterial LDL retention, which precedes and contributes to atherosclerosis development. Angiotensin II (angII) is the major bioactive peptide of the renin-angiotensin system. There are abundant data from animal studies showing that angII administration potentiates the development of atherosclerosis, and antagonism of either angII formation or its interaction with its major receptor AT1a attenuates lesion progression (1.Candido R. Jandeleit-Dahm K.A. Cao Z. Nesteroff S.P. Burns W.C. Twigg S.M. Dilley R.J. Cooper M.E. Allen T.J. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice.Circulation. 2002; 106: 246-253Crossref PubMed Scopus (244) Google Scholar, 2.Daugherty A. Cassis L. Chronic angiotensin II infusion promotes atherogenesis in low density lipoprotein receptor−/− mice.Ann. N. Y. Acad. Sci. 1999; 892: 108-118Crossref PubMed Scopus (158) Google Scholar, 3.Weiss D. Kools J.J. Taylor W.R. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice.Circulation. 2001; 103: 448-454Crossref PubMed Scopus (298) Google Scholar, 4.Keidar S. Heinrich R. Kaplan M. Hayek T. Aviram M. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDL: a possible role for interleukin-6.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1464-1469Crossref PubMed Scopus (105) Google Scholar, 5.Sugiyama F. Haraoka S. Watanabe T. Shiota N. Taniguchi K. Ueno Y. Tanimoto K. Murakami K. Fukamizu A. Yagami K. Acceleration of atherosclerotic lesions in transgenic mice with hypertension by the activated renin-angiotensin system.Lab. Invest. 1997; 76: 835-842PubMed Google Scholar). However, the mechanisms by which angII contributes to atherosclerosis development are not yet fully understood. Numerous studies support the notion that angII has multiple actions at various levels in the development of vascular lesions. The atherogenicity of angII has been ascribed to several effects of angII, including its proinflammatory properties and its effect in stimulating the proliferation of vascular smooth muscle cells (6.Dzau V.J. Theodore Cooper Lecture. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis.Hypertension. 2001; 37: 1047-1052Crossref PubMed Scopus (680) Google Scholar, 7.Prescott M.F. Webb R.L. Reidy M.A. Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury.Am. J. Pathol. 1991; 139: 1291-1296PubMed Google Scholar). AngII is known to stimulate the secretion of extracellular matrix (ECM) components by vascular smooth muscle cells, such as laminin, fibronectin, collagen, elastin, and proteoglycans (8.Figueroa J.E. Vijayagopal P. Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties.Atherosclerosis. 2002; 162: 261-268Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 9.Hahn A.W. Regenass S. Kern F. Buhler F.R. Resink T.J. Expression of soluble and insoluble fibronectin in rat aorta: effects of angiotensin II and endothelin-1.Biochem. Biophys. Res. Commun. 1993; 192: 189-197Crossref PubMed Scopus (35) Google Scholar, 10.Kato H. Suzuki H. Tajima S. Ogata Y. Tominaga T. Sato A. Saruta T. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells.J. Hypertens. 1991; 9: 17-22Crossref PubMed Scopus (288) Google Scholar, 11.Regenass S. Resink T.J. Kern F. Buhler F.R. Hahn A.W. Angiotensin-II-induced expression of laminin complex and laminin A-chain-related transcripts in vascular smooth muscle cells.J. Vasc. Res. 1994; 31: 163-172Crossref PubMed Scopus (14) Google Scholar, 12.Shimizu-Hirota R. Sasamura H. Mifune M. Nakaya H. Kuroda M. Hayashi M. Saruta T. Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors.J. Am. Soc. Nephrol. 2001; 12: 2609-2615PubMed Google Scholar). However, it is not known whether this stimulation of ECM components leads to increased LDL retention in the artery wall. As outlined in the “response-to-retention” hypothesis, the retention of atherogenic lipoprotein particles within the subendothelial space of the vascular wall is thought to be a critical step in the initiation of atherosclerosis (13.Williams K.J. Tabas I. The response-to-retention hypothesis of early atherogenesis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar). The interactions of LDL particles with ECM components facilitate changes of their structure, rendering them vulnerable to modification and uptake by macrophages (14.Sartipy P. Bondjers G. Hurt-Camejo E. Phospholipase A2 type II binds to extracellular matrix biglycan: modulation of its activity on LDL by colocalization in glycosaminoglycan matrixes.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1934-1941Crossref PubMed Scopus (53) Google Scholar). Apolipoprotein B (apoB), the major lipoprotein component of LDL, has been identified in close association with the vascular proteoglycans biglycan and decorin in human lesions (15.O'Brien K.D. Olin K.L. Alpers C.E. Chiu W. Hudkins K. Wight T.N. Chait A. Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: co-localization of biglycan with apolipoproteins.Circulation. 1998; 98: 519-527Crossref PubMed Scopus (243) Google Scholar, 16.Riessen R. Isner J.M. Blessing E. Loushin C. Nikol S. Wight T.N. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries.Am. J. Pathol. 1994; 144: 962-974PubMed Google Scholar, 17.Nakashima Y. Fujii H. Sumiyoshi S. Wight T.N. Sueishi K. Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1159-1165Crossref PubMed Scopus (306) Google Scholar), whereas in mouse atherosclerosis, apoB appears to colocalize with biglycan and perlecan (18.Kunjathoor V.V. Chiu D.S. O'Brien K.D. LeBoeuf R.C. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 462-468Crossref PubMed Scopus (103) Google Scholar). Proteoglycans bind lipoproteins via ionic interactions between negatively charged sulfate and carboxylic acid groups on the glycosaminoglycan chains with positively charged residues of apoB in the LDL particle (19.Boren J. Olin K. Lee I. Chait A. Wight T.N. Innerarity T.L. Identification of the principal proteoglycan-binding site in LDL: a single point mutation in apolipoprotein B100 severely affects proteoglycan interaction without affecting LDL receptor binding.J. Clin. Invest. 1998; 101: 2658-2664Crossref PubMed Scopus (224) Google Scholar, 20.Kovanen P.T. Pentikainen M.O. Decorin links low-density lipoproteins (LDL) to collagen: a novel mechanism for retention of LDL in the atherosclerotic plaque.Trends Cardiovasc. Med. 1999; 9: 86-91Crossref PubMed Scopus (49) Google Scholar). Studies have demonstrated that angII stimulates the synthesis of proteoglycans by cultured vascular smooth muscle cells, with one study demonstrating increased LDL binding affinity of proteoglycans synthesized by vascular smooth muscle cells stimulated with angII (8.Figueroa J.E. Vijayagopal P. Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties.Atherosclerosis. 2002; 162: 261-268Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 12.Shimizu-Hirota R. Sasamura H. Mifune M. Nakaya H. Kuroda M. Hayashi M. Saruta T. Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors.J. Am. Soc. Nephrol. 2001; 12: 2609-2615PubMed Google Scholar). The purpose of this study was to test the hypothesis that one mechanism by which angII induces atherosclerosis is via increased vascular proteoglycan synthesis with increased LDL retention in the artery wall. Cell culture media and additives were obtained from Invitrogen (Carlsbad, CA). All other reagents were from Sigma (St. Louis, MO) unless specified otherwise. Female low density lipoprotein receptor-deficient (LDLR−/−) mice (C57BL6 background) and AT1a−/− LDLR−/− mice (21.Daugherty A. Rateri D.L. Lu H. Inagami T. Cassis L.A. Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor.Circulation. 2004; 110: 3849-3857Crossref PubMed Scopus (212) Google Scholar) were kindly provided by Dr. Alan Daugherty at the University of Kentucky. LDLR−/− mice were selected as the model because they do not develop atherosclerosis over the short term unless fed a high-fat, high-cholesterol diet. Mice were housed in a temperature-controlled facility with 12 h light/dark cycles. Mice consumed normal rodent chow ad libitum and had free access to water. In some experiments, mice received 6 weeks of Western diet (0.15% cholesterol and 21% fat; Harlan Teklad, catalog No. 88137) to induce atherosclerosis development. Animal care and experimental procedures were approved by and performed in accordance with University of Kentucky and University of California, Davis, Animal Care Committee guidelines, in conformity with Public Health Service policy on the humane care and use of laboratory animals. Mice reaching 20 g (generally at 10–12 weeks old) received angII (1,000 ng/kg/min) or saline for up to 28 days via Alzet osmotic minipumps (model 2004; ALZA Scientific Products, Mountain View, CA) implanted subcutaneously in the scapular region, as described previously (22.Daugherty A. Manning M.W. Cassis L.A. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.J. Clin. Invest. 2000; 105: 1605-1612Crossref PubMed Scopus (1046) Google Scholar). In some experiments, mice were infused with lower doses of angII (250 or 500 ng/kg/min). To control for the effects of angII to induce hypertension, parallel groups received either norepinephrine (NE; 5.6 mg/kg/day), selected to mimic the blood pressure increase induced by angII (3.Weiss D. Kools J.J. Taylor W.R. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice.Circulation. 2001; 103: 448-454Crossref PubMed Scopus (298) Google Scholar), or its vehicle, 0.2% ascorbate. In some experiments, the pumps were removed after 28 days to ensure complete cessation of infusions, then the mice were fed an atherogenic Western diet for the next 6 weeks. Systolic blood pressure was measured four to five times per week in conscious mice using an automatic tail cuff apparatus coupled to a personal computer-based data-acquisition system (RTBP1007; Kent Scientific, Litchfield, CT), with each measurement performed at the same time of day by the same operator. For each measurement, 10 chronological readings were obtained from each mouse to yield a mean blood pressure value for the day. Before pump implantation, mice were acclimatized to the system through 1 week of baseline blood pressure measurements. Serum total cholesterol concentrations were determined using an enzymatic cholesterol assay kit (Wako Chemical Co., Richmond, VA). Lipoprotein cholesterol distributions were evaluated in individual serum samples (50 μl) from three mice in each group after fractionation by fast-protein liquid chromatography gel filtration (Pharmacia LKB Biotechnology, Uppsala, Sweden) on a single Superose 6 column (23.Cole T.G. Kitchens R. Daugherty A. Schonfeld G. An improved method for separation of triglyceride-rich lipoproteins by FPLC.Pharmacia Biocommunique. 1990; 4: 4-6Google Scholar). Fractions were collected and cholesterol concentrations were determined with the cholesterol assay kit mentioned above. Transforming growth factor (TGF)-β was quantified in plasma collected after 3 days of infusions, with the TGF-β1 Emax® ImmunoAssay System (Promega, Madison, WI) according to the manufacturer's directions. Samples were acid-activated before quantification. LDL isolation was performed according to the method of Sattler, Mohr, and Stocker (24.Sattler W. Mohr D. Stocker R. Rapid isolation of lipoproteins and assessment of their peroxidation by high-performance liquid chromatography postcolumn chemiluminescence.Methods Enzymol. 1994; 233: 469-489Crossref PubMed Scopus (283) Google Scholar), and LDL protein was labeled with Alexa Fluor 546 (Molecular Probes, Eugene, OR) as described by the manufacturer's protocol (25.Pitas R.E. Innerarity T.L. Weinstein J.N. Mahley R.W. Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy.Arteriosclerosis. 1981; 1: 177-185Crossref PubMed Google Scholar). Briefly, postprandial blood samples were obtained from healthy volunteers at 3.5 h after consumption of a high-fat meal. These studies were approved by the Institutional Review Board of the University of California, Davis. LDL (d = 1.01–1.06 g/ml) was isolated from human plasma and obtained by sequential density gradient ultracentrifugation for 18 h at 14°C at 40,000 rpm in a 50.4Ti rotor. The labeled LDL (∼2 mg protein/ml) was diluted in Krebs-Henseleit solution (final concentration, ∼50 μg/ml) for use in these experiments. Mice were anesthetized with intraperitoneal injection of pentobarbital (50 mg/kg body weight). The carotid arteries from the mice were dissected, cannulated, removed, and placed in a microscope viewing chamber, as described previously (26.Walsh B.A. Mullick A.E. Walzem R.L. Rutledge J.C. 17Beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall.J. Lipid Res. 1999; 40: 387-396Abstract Full Text Full Text PDF PubMed Google Scholar). Briefly, the vessels were alternately perfused with fluorescently labeled LDL and nonfluorescent buffer solution at a rate of 1.5 ml/min in physiological flow direction, pH, temperature, and pressure; thus, each artery serves as its own control. The nonfluorescent buffer was 1% BSA-Krebs-Henseleit buffer, and the perfusate contained 50 μg/ml fluorescently labeled LDL molecules. LDL accumulation was quantified during the washout phase as described previously (26.Walsh B.A. Mullick A.E. Walzem R.L. Rutledge J.C. 17Beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall.J. Lipid Res. 1999; 40: 387-396Abstract Full Text Full Text PDF PubMed Google Scholar). Immunohistochemical staining was performed as described previously (22.Daugherty A. Manning M.W. Cassis L.A. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.J. Clin. Invest. 2000; 105: 1605-1612Crossref PubMed Scopus (1046) Google Scholar). Briefly, serial frozen sections (8 μm thick) were stained. The primary antibodies used were as follows: LF-159 for biglycan and LF-113 for decorin (both polyclonal, 1:200 dilution; generously provided by Dr. Larry Fisher, National Institutes of Health); K23300R for apoB (polyclonal, 1:50 dilution; which recognizes both mouse apoB-48 and human apoB-100; BioDesign, Saco, ME); and AB1033 for versican (polyclonal, 1:200 dilution; Chemicon, Temecula, CA). Perlecan was detected using RT-794-B1 (monoclonal, biotinylated, 1:100 dilution; Lab Vision-NeoMarkers, Fremont, CA). No biotinylated secondary antibody was needed for perlecan detection during the process. Negative controls were obtained with isotype-matched irrelevant antibodies, no primary antibody, or no secondary antibody. Thoracic aortas were stripped of adventitia, total protein was extracted and dissolved in 1% SDS, and concentration was determined by the method of Lowry et al. (27.Lowry O.H. Rosebrough N.J. Farr A.L. Randall R.J. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 1951; 193: 265-275Abstract Full Text PDF PubMed Google Scholar). Equal amounts of protein were separated by SDS-PAGE using 10% gels and then transferred to polyvinylidene fluoride membranes in 20% methanol. Membranes were blocked in 5% nonfat milk and 0.1% Tween-20, then probed with antibodies against mouse biglycan (1:1,000 dilution; LF-159; National Institutes of Health). HRP-labeled secondary antibody was used at 1:25,000 dilution and detected using SuperSignal West Pico (34080; Pierce, Rockford, IL). Blotting for β-actin (ab8227; Abcam, Inc., Cambridge, MA) served as a loading control. Vascular smooth muscle cells isolated from rat (generously provided by Dennis Bruemmer, University of Kentucky) were cultured as described previously (28.Bruemmer D. Yin F. Liu J. Kiyono T. Fleck E. Van Herle A.J. Law R.E. Expression of minichromosome maintenance proteins in vascular smooth muscle cells is ERK/MAPK dependent.Exp. Cell Res. 2003; 290: 28-37Crossref PubMed Scopus (16) Google Scholar). After reaching confluence, the cells were serum-deprived (0.1%) for 48 h, then stimulated with angII (1 μmol/l) or saline, in the presence or absence of losartan (1 μg/ml), TGF-β neutralizing antibody 1D11 (10 μg/ml) (29.Dasch J.R. Pace D.R. Waegell W. Inenaga D. Ellingsworth L. Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification.J. Immunol. 1989; 142: 1536-1541PubMed Google Scholar), or irrelevant antibody 13C4 (10 μg/ml; both R&D Systems, Minneapolis, MN) for 24 h. Cells were metabolically labeled with 35SO4 (100 μCi/ml) for the 24 h period. Sulfate incorporation into secreted proteoglycans was quantified using cetyl pyridinium chloride precipitation as described previously (30.Schonherr E. Jarvelainen H.T. Kinsella M.G. Sandell L.J. Wight T.N. Platelet derived growth factor and transforming growth factor-beta1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells.Arterioscler. Thromb. 1993; 13: 1026-1036Crossref PubMed Google Scholar). The cell layer was washed with saline, then cell protein was quantified using a bicinchoninic acid protein assay kit (Bio-Rad, Hercules, CA). Sulfate incorporation was adjusted for cell protein content. The medium was collected, and secreted proteoglycans were concentrated and purified using separate DEAE-Sephacel minicolumns as described previously (30.Schonherr E. Jarvelainen H.T. Kinsella M.G. Sandell L.J. Wight T.N. Platelet derived growth factor and transforming growth factor-beta1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells.Arterioscler. Thromb. 1993; 13: 1026-1036Crossref PubMed Google Scholar, 31.Schonherr E. Jarvelainen H.T. Sandell L.J. Wight T.N. Effects of platelet-derived growth factor and transforming growth factor, beta1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells.J. Biol. Chem. 1991; 266: 17640-17647Abstract Full Text PDF PubMed Google Scholar). To estimate molecular weight, equal counts were applied to SDS-PAGE gels (3.5% stacking gel and 4–12% gradient resolving gel) (30.Schonherr E. Jarvelainen H.T. Kinsella M.G. Sandell L.J. Wight T.N. Platelet derived growth factor and transforming growth factor-beta1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells.Arterioscler. Thromb. 1993; 13: 1026-1036Crossref PubMed Google Scholar, 31.Schonherr E. Jarvelainen H.T. Sandell L.J. Wight T.N. Effects of platelet-derived growth factor and transforming growth factor, beta1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells.J. Biol. Chem. 1991; 266: 17640-17647Abstract Full Text PDF PubMed Google Scholar). Radiolabeled molecular weight markers were run in a parallel lane. Parallel wells were treated identically except without the metabolic labeling, and Western blot analysis was performed on the conditioned medium, as described above. Atherosclerosis was quantified in three vascular beds: the aortic root, the aortic intimal surface, and the brachiocephalic artery (32.Williams H. Johnson J.L. Carson K.G. Jackson C.L. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 788-792Crossref PubMed Scopus (196) Google Scholar). Aortic root sections (8 μm thick) collected every 72 μm and brachiocephalic artery sections (5 μm thick) collected every 125 μm were stained with Oil Red O and quantified using computer-assisted morphometry, as described previously (33.Daugherty A. Whitman S.C. Quantification of atherosclerosis in mice.Methods Mol. Biol. 2003; 209: 293-309PubMed Google Scholar). Aortic intimal surface lesions were evaluated by en face quantification of lesions as detailed previously (33.Daugherty A. Whitman S.C. Quantification of atherosclerosis in mice.Methods Mol. Biol. 2003; 209: 293-309PubMed Google Scholar). All quantifications were performed in duplicate by observers blinded to the group assignments of the mice. Statistical differences of the experimental data were first assessed by one-way nonparametric ANOVA, followed by Dunn's multiple comparison test if a significant group difference was detected. All analyses were performed with SigmaStat (Jandel Scientific, San Rafael, CA). All data are normally distributed and presented as means ± SEM, except for that in Fig. 4, in which individual data points are shown. P < 0.05 was considered statistically significant. To determine whether angII stimulates arterial LDL retention, LDLR−/− mice were infused with angII (1,000 ng/kg/min) or saline for 4 weeks. Because angII infusions induce hypertension, parallel groups of littermate mice were infused with NE (5.6 mg/kg/min), which induces a similar degree of hypertension as does angII (3.Weiss D. Kools J.J. Taylor W.R. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice.Circulation. 2001; 103: 448-454Crossref PubMed Scopus (298) Google Scholar). During the infusion period, mice were fed normal laboratory chow, which does not stimulate atherosclerosis development. At the end of the infusion period, carotid arteries were isolated and perfused with LDL ex vivo. Carotid arteries from mice that received angII had a significantly higher rate of LDL retention (P = 0.0006) compared with carotid arteries from saline- or NE- infused littermate controls (Fig. 1). To determine whether this increase in arterial LDL retention was mediated by proteoglycans, adjacent sections of the perfused carotids were stained for apoB and the major vascular proteoglycans biglycan, perlecan, and decorin. Both biglycan and decorin exhibited strong staining in the adventitia in all groups, but carotids from angII-infused mice consistently demonstrated increased medial content of biglycan (Fig. 2A). Perlecan stained strongly in all mouse carotids, but total vascular content appeared to be increased in angII-infused mouse carotids compared with saline- or NE-infused mouse carotids (Fig. 2A). ApoB was detected in carotids from angII- and NE-infused mice, but not from saline-infused mice, and colocalized with both biglycan and perlecan, but not with decorin (Fig. 2). To confirm the immunohistochemical data, aortic protein was collected after 28 days of infusions and Western blot analysis demonstrated increased content of biglycan (Fig. 2B). Perlecan could not be evaluated by Western blot because of poor transfer. No difference was seen in decorin content between angII-, saline-, and NE-infused mice (data not shown). To elicit mechanisms by which angII stimulates biglycan expression, mice were infused with saline or angII at 250, 500, or 1,000 ng/kg/min for 28 days. AngII increased blood pressure in a dose-dependent manner (average systolic blood pressure by group was 114, 129, 155, and 165 mm Hg for saline and angII at 250, 500, and 1,000 ng/kg/min, respectively; P < 0.001). AngII stimulated aortic biglycan content in a dose-dependent manner (Fig. 3A). AngII has been proposed to stimulate biglycan synthesis via increased TGF-β concentrations (34.Tiede K. Stoter K. Petrik C. Chen W.B. Ungefroren H. Kruse M.L. Stoll M. Unger T. Fischer J.W. Angiotensin II AT(1)-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFbeta in vitro.Cardiovasc. Res. 2003; 60: 538-546Crossref PubMed Scopus (25) Google Scholar), and we and others have reported previously that TGF-β increases the synthesis of vascular proteoglycans, especially biglycan, and increases proteoglycan LDL binding affinity (30.Schonherr E. Jarvelainen H.T. Kinsella M.G. Sandell L.J. Wight T.N. Platelet derived growth factor and transforming growth factor-beta1 differentially affect the synthesis of biglycan and decorin by monkey arterial smooth muscle cells.Arterioscler. Thromb. 1993; 13: 1026-1036Crossref PubMed Google Scholar, 31.Schonherr E. Jarvelainen H.T. Sandell L.J. Wight T.N. Effects of platelet-derived growth factor and transforming growth factor, beta1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells.J. Biol. Chem. 1991; 266: 17640-17647Abstract Full Text PDF PubMed Google Scholar, 35.Little P.J. Tannock L. Olin K.L. Chait A. Wight T.N. Proteoglycans synthesized by arterial smooth muscle cells in the presence of transforming growth factor-beta1 exhibit increased binding to LDLs.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 55-60Crossref PubMed Scopus (123) Google Scholar). Plasma TGF-β concentrations quantified after 3 days of infusions were increased by angII in a dose-dependent manner (Fig. 3B). To determine whether TGF-β was required for angII stimulation of biglycan, vascular smooth muscle cells in culture were stimulated with angII (1 μmol/l) in the presence or absence of an irrelevant antibody or a TGF-β-neutralizing antibody (13C4 and 1D11, respectively) (29.Dasch J.R. Pace D.R. Waegell W. Inenaga D. Ellingsworth L. Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification.J. Immunol. 1989; 142: 1536-1541PubMed Google Scholar). AngII exposure to cells caused increased total proteoglycan synthesis, as indicated by relative sulfate incorporation, and increased proteoglycan size; 13C4 had no effect, but the angII stimulation of sulfate incorporation and size was inhibited by 1D11 (Fig. 3C, D). Western blot analysis revealed stimulation of biglycan by angII, which was partially inhibited by 13C4 but completely inhibited by 1D11 and losartan (Fig. 3E). Losartan also inhibited the effect of angII to stimulate increased proteoglycan synthesis and size (Fig. 3C, D). AngII infusion of AT1a−/− LDLR−/− mice did not stimulate biglycan content (Fig. 3E), demonstrating that the presence of the AT1a receptor is required for angII to stimulate biglycan. To determine whether the induction of vascular biglycan content and the stimulation of LDL retention predisposed to accelerated atherosclerosis, mice received infusions" @default.
• W2037641639 created "2016-06-24" @default.
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• W2037641639 date "2008-03-01" @default.
• W2037641639 modified "2023-10-03" @default.
• W2037641639 title "Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development" @default.
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