Published online before print August 11, 2005, doi: 10.1161/01.ATV.0000181763.57495.2b
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© 2005 American Heart Association, Inc.
Vascular Biology |
Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats
From the Department of Cardiovascular Medicine (N.I., K.S., G.M., M.O., R.N.), University of Tokyo Graduate School of Medicine, and the Department of Pathology, Wakayama Medical College (I.M.), Japan.
Correspondence to Dr Nobukazu Ishizaka, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky{at}umin.ac.jp
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Abstract |
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Objective— We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II-infused animals.
Methods and Results— Sprague-Dawley rats were given Ang II for 7 days via subcutaneously implanted osmotic minipumps. Ang II infusion caused a >20-fold increase in ferritin protein expression over control values. Immunohistochemistry showed that Ang II infusion markedly increased the ferritin expression in the aortic endothelial and adventitial cells, with some of the latter being identified as monocytes/macrophages. Prussian blue staining showed that stainable iron was observed in the adventitial layer of aorta from Ang II-infused animals, but not in the endothelial layer. Chelation of iron suppressed aortic induction of ferritin and also the oxidative stress markers, heme oxygenase-1 and 4-hydroxynonenal-modified protein adducts. In addition, iron chelation attenuated Ang II-induced impairment of aortic relaxations in response to acetylcholine and sodium nitroprusside and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1. Iron chelation also partially attenuated the medial thickening and perivascular fibrosis induced by Ang II infusion for 4 weeks.
Conclusion— Ang II infusion caused ferritin induction and iron deposition in the aortas. These phenomena might have a role in the regulation of gene expression, impairment of vascular function, and arterial remodeling induced by Ang II, which are presumably mediated in part by enhancement of oxidative stress.
We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II–infused animals. Ang II infusion caused ferritin induction and iron deposition in the aortas. These phenomena might have a role in the regulation of gene expression, impairment of vascular function, and arterial remodeling induced by Ang II, which are presumably mediated in part by enhancement of oxidative stress.
Key Words: ferritin • heme oxygenase • hypertension • oxidative stress • vascular relaxation
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Introduction |
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Several previous studies have shown that ferritin expression is induced and iron accumulation is present in the atherosclerotic lesions in animal models and in humans.1–5 The findings that treatment with iron chelators results in improved vascular endothelial function,6,7 and that both iron chelation and restriction of iron intake reduce atheroma formation in atherosclerosis-prone animals8,9 suggest that altered iron homeostasis in the body or in the vascular wall may play a role in the atherogenic processes and in impairment of vascular reactivity. The proposed mechanisms underlying iron-mediated vascular damage include platelet activation,10 promotion of vascular cell proliferation,11 and enhancement of oxidative stress by iron-catalyzed hydroxyl radical formation via Fenton chemistry and subsequent lipid peroxidation.12
See page 2235
In previous studies, we have reported that long-term administration of angiotensin II (Ang II) in rats caused accumulation of iron in the kidney,13,14 heart,15 and liver,16 and that this may play a role in regulating the gene expression and function in these organs. Thus far, little is known about whether Ang II induces aberrant iron homeostasis in the vascular tissue; however, if so, it might exacerbate the oxidant-induced vascular damage initiated by increased production of superoxide17 generated by activated NAD(P)H oxidase.18 In this context, it may be of note that iron chelation decreased the extent of in vivo oxidative stress in animals with long-term Ang II infusion.19,20
In the present study, we have investigated the extent of iron accumulation and ferritin induction in the aortas of Ang II-infused animals, and the possible relationship between these phenomena, modulation of gene expression, and vascular function and remodeling.
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Methods |
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Animal Models
The experiments were performed in accordance with the guidelines for animal experimentation approved by the Animal Center for Biomedical Research, Faculty of Medicine, University of Tokyo. Ang II-induced hypertension was induced in male Sprague-Dawley rats by subcutaneous implantation of an osmotic minipump (Alzet model 2001; Alza Pharmaceutical, Palo Alto, Calif) as described previously.21 Briefly, Val5–Ang II (Sigma Chemical, St Louis, Mo) was infused at a dose of 0.7 mg/kg per day for 7 days, which significantly increased the blood pressure of rats (192±4 mm Hg, n=10, P<0.01 versus control rats, 131±3 mm Hg, n=6). To contrast this model with another model of hypertension, norepinephrine (Sigma Chemical) was infused at a rate of 2.8 mg/kg per day, which resulted in a comparable hypertensive effects (196±6 mm Hg, n=9) to those of Ang II.21 Ang II was infused 0.7 mg/kg per day in the current experiments unless stated otherwise. Subpressor dose of Ang II was a dose of 0.25 mg/kg per day, which did not significantly increase the systolic blood pressure of rats as compared with untreated rats (134±3 mm Hg, n=6).
Iron chelator, deferoxamine (a kind gift from Novartis) was subcutaneously administered at a dose of 200 mg/kg per day, which did not significantly affect the blood pressure of Ang II-infused rats (196±7 mm Hg, n=9). Iron-overload was achieved by 4 intraperitoneal injections of an iron–dextran complex (a kind gift from Teikoku Hormone Mfg, Tokyo, Japan) at a dose of 240 mg of elemental iron/kg, which did not significantly alter the blood pressure (131±3 mm Hg, n=10) compared with untreated control.
Protein Purification and Western Blot Analysis
Protein was isolated by homogenizing samples in the lysis buffer containing protease inhibitors as described previously.21 Polyclonal antibodies against rat ferritin (Panapharm, Kumamoto, Japan) and heme oxygenase-1 (HO-1) (StressGen, Victoria, BC, Canada), and monoclonal antibody against ß-actin (Sigma) and 4-hydroxynonenal (HNE)-modified protein (NOF, Tokyo, Japan) were used at dilutions of 1/1000, 1/2000, 1/2000, and 1/3000, respectively.15 The ECL Western blotting system (Amersham Life Sciences, Arlington Heights, Ill) was used for detection. Bands were visualized by a lumino-analyzer (Fuji Photo Film, Tokyo, Japan). Band intensity was calculated and is expressed as a percentage of the control value.
Histological and Immunohistochemical Analyses
For histological and immunohistochemical analyses, formalin-fixed paraffin-embedded specimen was used except in the cases of staining for HNE-modified proteins and for monocyte chemoattractant protein-1 (MCP-1), in which Bouin-fixed paraffin-embedded specimen and unfixed frozen sections, respectively, were used. Immunohistochemistry was performed as described previously.15 Primary antibodies against rat macrophage/monocyte (ED-1; Chemicon International, Temecula, Calif), human 
-smooth muscle actin (Sigma Chemical), rat ferritin, HNE-modified proteins, and rat MCP-1 (IBL, Gunma, Japan) were used at dilutions of 1/200, 1/1,000, 1/200, 1/50, and 1/100, respectively. In some immunohistochemical studies, relevant pre-immune IgG controls were used as control antibodies. For immunofluorescence staining, rhodamine-conjugated anti-mouse (Chemicon International) and fluorescein-conjugated anti-rabbit (Sigma Chemical) antibodies were used at a dilution of 1/100. Laser scanning confocal fluorescence microscopy combined with differential interference contrast imaging was performed using FLUOVIEW FV300 (Olympus, Tokyo, Japan). Tissue iron content was analyzed with atomic absorption spectrophotometry.
Isolated Vascular Ring Experiments
Ring segments (5 mm in length) of the thoracic aorta were suspended in individual organ chambers filled with Krebs buffer of the following composition (mmol/L): NaCl, 118.3; KCl, 4.7; CaCl2, 2.5; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 25.0; and glucose, 10, pH 7.4. The solution was continuously aerated with a 95% O2, 5% CO2 mixture, which was maintained at 37°C. Isometric tension was recorded by using an isometric force displacement transducer (NIHON KOHDEN, Tokyo, Japan) connected to a data acquisition system (Power Laboratory Chart 5; AD Instruments, Colo). The vessels were then precontracted with phenylephrine (3x10–6 mol/L). After a stable contraction plateau was reached, the rings were exposed to either acetylcholine or sodium nitroprusside (SNP).
RNA Extraction, Northern Blot Analysis, and Real-Time Reverse-Transcription Polymerase Chain Reaction
Total RNA was isolated from homogenized aorta by the acid guanidinium thiocyanate-phenol chloroform method as described previously.22 Probes were obtained by polymerase chain reaction (PCR) with reverse-transcription using the primers 5'-CAGGTCTCTGTCACGCTTCT-3' and 5'-AGTATTCATGGAAGGGAATAG-3' for MCP-1. The reverse-transcription PCR product was subcloned into a p-GEM-T vector (Promega, Madison, Wis), and the cDNA was confirmed as rat MCP-1 by direct sequencing. For Northern blotting, a rat MCP-1 cDNA probe was labeled with [-32P]-dCTP by a DNA labeling kit (Nippon Gene, Tokyo, Japan), and hybridized at 42°C overnight.
To investigate the mRNA expression of transferrin receptor, H-ferritin, and L-ferritin, real-time quantitative PCR with gene-specific hybriprobes was performed by LightCycler (Roche Diagnostics, Basel, Switzerland) after first-strand cDNA was synthesized with 2 µg of total RNA as a template using a SuperScript First-Strand Synthesis System (Invitrogen, Carlsbad, Calif). The used primer sets were as follows: Transferrin receptor, sense primer, 5'- GGA GAC TAC TTC CGT GCT ACT T-3', antisense primer, 5'- AGA GCC CCA GAA GAT GTG TC-3'; H-ferritin, sense primer, 5'- CAA ACT GGC TAC TGA CAA GAA T-3' antisense primer, 5'- TGGAGCGCATCCACTTGA-3'; L-ferritin, sense primer, 5'-AAG TGG AAG CTG CCG TGA A-3', antisense primer, 5'-CTG CAA CTT GAG GAG ACG C-3'. The mRNA expression of these genes were normalized to GAPDH mRNA expression, which was also assessed by the real-time PCR with sense primer 5'-TGA ACG GGA AGC trichloroacetic acid CTG G-3', and antisense primer 5'= TCC ACC ACC CTG TTG CTG TA-3' and presented as the percentages of the data from aortas of untreated animals.
Remodeling of Aortic Wall
The degree of vascular remodeling (the medial thickness and perivascular fibrosis) was estimated in the aortas of the rat subjected Ang II administration at a dose of 0.7 mg/kg per day for 28 days. Some rats were given subcutaneous infusion of deferoxamine at a dose of 200 mg/kg per day for the last 14 days. Aortas were perfused with physiological saline solution and fixed with 6% formaldehyde solution for 30 minutes via infusion into the left ventricle at a pressure of 90 mm Hg. Thoracic aorta was cut into six pieces after excised. The paraffin-embedded specimens in the 2 mm of thickness were stained with hematoxylin and eosin and Masson’s trichrome staining. To evaluated vascular wall thickness, the wall-to-lumen ratio of the aorta was examined, and for perivascular fibrosis, fibrosis area was measured as described previously15,23 and calculated as perivascular fibrosis surrounding the vessel wall to the vessel area. Histopathology and morphometry were performed by investigators who were unaware of the treatment being administered.
Statistical Analysis
Data are expressed as the mean±SEM. We used ANOVA followed by a multiple comparison test to compare raw data, before expressing the results as a percentage of the control value using the statistical analysis software Statistica version 5.1 J for Windows (StatSoft Inc, Tulsa, Okla). A value of P<0.05 was considered to be statistically significant
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Treatment of Ang II, Norepinephrine, Deferoxamine, and Iron Dextran on Aortic Expression of Ferritin and HO-1
Administration of pressor dose Ang II for 7 days increased aortic ferritin expression &25-fold over control values. Non-pressor dose Ang II and pressor dose of norepinephrine also increased aortic ferritin expression, although to a significantly lesser extent (Figure 1). The pattern of regulation of HO-1 by these Ang II and norepinephrine was similar to that of ferritin. Treatment of Ang II-infused rats with deferoxamine partially suppressed upregulation of ferritin and HO-1. Iron overload achieved by the administration of iron dextran, which increases the serum iron levels &90-fold over control values,24 caused induction of ferritin to a similar extent as Ang II; however, it did not significantly increase aortic HO-1 expression (Figure 1).
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P<0.01 vs untreated control.
Localization of Ferritin and Iron Deposition
Immunohistochemical analysis showed that ferritin was expressed mainly in the aortic endothelial cells and only weakly in the adventitial cells in untreated control rats, and ferritin expression appeared to be enhanced after Ang II infusion (Figure 2A through 2F). Confocal microscopy showed that some of the ferritin-positive cells were also positive for ED-1, thus monocytes/macrophages (Figure 2G). Iron was not histologically evident by Prussian blue staining in the aorta of untreated rats (Figure 2H). After 7 days of Ang II infusion, some of the adventitial cells were found to be positive for iron, although stainable iron was not evident in the endothelium (Figure 2I). No apparent iron deposition could be observed in the aortas of rats treated with both Ang II and an iron chelator (Figure 2J). In the aortas of rats treated with iron dextran, iron deposition could be observed both in the adventitial and endothelial cells (Figure 2K). Staining of serial sections showed that iron positive cells in the adventitial layer were positive for ferritin (Figure 2L and 2M). Of ferritin-positive adventitial cells, 7.4±2.0% of such cells were found to be positive for stainable iron (number of rats=6). Iron-positive adventitial cells were also positive for ED-1 (Figure 2N and 2O), thus they were judged to be monocytes/macrophages.
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Tissue iron content in the aortas in the untreated animals were 58.1±3.0 µg/g dry weight (n=4). Ang II treatment significantly increased the aortic iron content (121.7±19.8 µg/g dry weight, n=9, P<0.05 versus untreated control), which was reversed by the treatment with deferoxamine (n=4) (Ang II plus deferoxamine, 52.6±5.3 µg/g dry weight, P=nonsignificant versus untreated control).
Localization and Expression of HNE-Modified Proteins
We next examined the expression HNE-modified protein adducts, markers of lipid peroxidation. Western blot analysis showed that a major band of HNE-protein adducts could be observed mainly at sizes of &30 and 70 kDa, and intensity of both of these bands were robustly increased after Ang II infusion (Figure 3A and 3B). Subpressor dose Ang II and norepinephrine also increased the amount of HNE-modified proteins, although to significantly lesser extent than pressor dose Ang II. Chelation of iron suppressed the increase in HNE-modified proteins induced by Ang II. Iron dextran treatment did not significantly alter the expression of HNE-modified proteins.
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We then examined the distribution of HNE-modified protein adducts by immunohistochemistry. In the aortas of untreated rat, expression of HNE-modified proteins was observed weakly in all layers of the aorta (Figure 3C). After Ang II infusion, staining of HNE-modified proteins was more intense especially in the endothelial and adventitial cells (Figure 3D). This Ang II-induced increase was reversed by the concomitant administration of deferoxamine (Figure 3E). Confocal microscopy showed that the adventitial cells with increased HNE-modified protein adducts were positive for ferritin (Figure 3G through 3N).
Relaxations of Aortic Segments
Peak relaxation produced by acetylcholine in aortas from Ang II-treated animals (50.4±5.7%, n=8) was significantly reduced compared with untreated rats (98.5±5.1%, n=8). Treatment with deferoxamine reversed, although only partially, the impaired vascular relaxation in response to acetylcholine in Ang II-treated animals (69.2±6.0%, n=10) (Figure 4A). Ang II treatment also blunted peak relaxation induced by SNP, which was again suppressed by the deferoxamine treatment (Figure 4B).
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Effects of Chelation of Iron in the Ang II-Induced Upregulation of MCP-1 in the Aorta
We showed previously that Ang II increases the expression of the MCP-1 in rat aorta.25 Here we examined the effects of iron chelation on Ang II-induced aortic MCP-1 upregulation. Ang II increased aortic expression &3-fold over control, which was partially suppressed by treatment with deferoxamine (Figure 5). However, iron dextran did not significantly affect MCP-1 expression. Then localization of MCP-1 was investigated using antibody against rat MCP-1. As shown in Figure 5C through 5H, expression of MCP-1 protein was increased mainly in the medial layer smooth muscle cells in the aortas of Ang II-infused animals.
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Effect of Iron Chelation on Ang II-Induced Remodeling of Aortic Wall
We next examined whether deferoxamine have any effects on Ang II-induced vascular remodeling. For this purpose, Ang II was administered for 28 days, and some rats were given deferoxamine for 14 consecutive days starting 14 days after the initiation of Ang II infusion. Systolic blood pressure of rats received Ang II alone and Ang II plus deferoxamine were 196±11 mm Hg and 196±6 mm Hg, respectively (P=nonsignificant). Compared with untreated control, Ang II infusion significantly increased the wall-to-lumen ratio from 0.22±0.01 (n=6) to 0.39±0.01 (n=8) (P<0.0001), which was partially suppressed by concomitant administration of DFO (0.35±0.01, n=10, P<0.001 versus control and P<0.01 versus Ang II-infused animals). Ang II infusion also increased the area of perivascular fibrosis compared with untreated control (control, 0.11±0.01 [n=6]; Ang II 0.23±0.012 [n=8], P<0.001), and these increases were again in part inhibited by the deferoxamine treatment (0.16±0.01, n=10, P<0.01 versus control, and P<0.01 versus Ang II-infused animals) (Figure 6).
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Expression of Transferrin Receptor, H-ferritin, and L-ferritin
Finally, we evaluated whether mRNA levels of transferrin receptor, H-ferritin, and L-ferritin were regulated in the aortas of Ang II-infused animals. Compared with the aortas of untreated-animals (n=15) (transferrin receptor 100±18%; H-ferritin 100±12%; L-ferritin 100±7%), mRNA expression of all these tested genes in the aortas of Ang II-infused animals (n=13) were found to be significantly greater (transferrin receptor 313±50%, P<0.0001; H-ferritin 137±15%, P<0.05; L-ferritin 161±17%, P<0.01).
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Discussion |
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In the present study, we have demonstrated that long-term administration of Ang II caused upregulation of ferritin expression and deposition of iron in the aortic wall of rats. Ang II also increased the expression of oxidative stress markers, HO-1 and HNE-modified proteins. Chelation of iron partially suppressed Ang II-induced upregulation of ferritin, HO-1, and HNE-modified proteins. In addition, iron chelation also partially reversed the impaired vascular relaxation in response to acetylcholine and SNP, and upregulation of MCP-1 mRNA induced by Ang II. These data collectively suggest that changes in iron homeostasis may in part contribute to the regulation of aortic gene expression and alteration of vascular function induced by long-term administration of Ang II.
Increased ferritin expression in the vasculature and its potential physiological importance have been demonstrated in several previous articles. Pang et al have reported that ferritin expression was increased in atherosclerotic aortas from animals and humans compared with nonatherosclerotic counterparts.3 Interestingly, there are some similar histological and immunohistological findings between in the early atherosclerotic lesions reported in Pang et al’s study and in the aortas of Ang II-infused animals in the present investigation, namely an increased expression of ferritin was observed in the endothelial cells and macrophages.3 In addition, this group and others also reported that expression of HO-1 was increased in the endothelial cells and macrophages in the atherosclerotic lesions,26,27 and we also found that expression of HO-1 was upregulated in the aortas of Ang II-infused animals in both a previous report21 and the current one. In addition, Lee et al have demonstrated a close association between iron deposition and the progression of atherosclerosis in the atherosclerosis-prone animal models, and have noted that restriction of iron intake inhibited lesion formation in these animals.9 In the current study, Ang II upregulated aortic expression of MCP-1, a chemokine that is postulated to play a central role in vascular damage and atherogenesis,28 and this was inhibited by iron chelation may support this notion. From these observations, it seems possible that ferritin induction and iron accumulation in the aortic wall may have a role in potentiating the pro-atherogenic properties of Ang II.
In the present study, iron chelation, although partially, suppressed the Ang II-induced impaired vascular relaxation in response to acetylcholine and SNP. This finding suggests that altered ferritin induction and/or iron deposition may have a role in modulating vascular function in Ang II-infused animals. It is noteworthy that effects of iron chelation in preventing vascular dysfunction in some diseased conditions, such as diabetes, have also been reported in some previous articles.12,29 Acetylcholine-induced vascular relaxation has also been shown to be significantly attenuated by hydroxyl radicals generated by Fenton reagents.30 These findings may collectively support the notion that the effects of iron chelation in attenuating Ang II-induced vascular dysfunction may relate to a reduction in the extent of oxidative stress, presumably a function of iron-catalyzed generation of hydroxyl radicals via Fenton chemistry.
We also found that deferoxamine inhibited arterial remodeling, that is the medial thickening and perivascular fibrosis, in the aortas of rats receiving Ang II infusion for 4 weeks. It has been reported recently that iron chelation, as well as adenovirus-mediated introduction of catalase decreased the extent of cardiac hypertrophy induced by serotonin.31 In addition, hypertrophic effects of glycosylated oxyhemoglobin on vascular smooth muscle cells could be suppressed by deferoxamine, as well as superoxide dismutase and catalase.32 These data suggest that iron may play a crucial role in the development of hypertrophy of cardiovascular system through reducing the production of toxic oxygen free radicals. Recent studies also suggested that iron and/or iron-mediated increase in the extent of oxidative stress play a role in the fibrotic changes not only in the liver16,33 but also in other organs such as heart.34,35 Our data may suggest the possibility that iron may also have a role in the vascular remodeling in vivo in certain diseased conditions, such as increased circulating Ang II.
We demonstrated that Ang II infusion increased the expression of 2 oxidative stress markers, HO-136 and HNE-modified proteins, and both were suppressed by iron chelation. Although these data are compatible to the notion that deferoxamine reduced the extent of oxidative stress induced by Ang II, one has to be also aware of the possible alternative scenario that deferoxamine may have directly reduced HO-1 expression by inducing Bach1, a heme-regulated transcriptional repressor for HO-1.37
In the current study, we showed that Ang II increased the ferritin expression and iron content of the aorta and that aortic expression of transferrin receptor was increased. Intracellular iron content may be affected by the transferrin receptor-mediated uptake of iron. It has been reported that exposure of vascular cells as well as fibroblasts to hydrogen peroxide increased the expression of transferrin receptor.38,39 Ang II stimulation may result in an enhancement of the degree of oxidative stress by activating membrane NADH oxidase,18 and in an increase in the hydrogen peroxide concentration of vascular cells.40 Thus, it is possible that increased oxidative stress evoked by Ang II induced aortic expression transferrin receptor, which resulted in increased aortic iron content. Until now, the expression and regulation of several genes related to iron metabolism,41 such as divalent metal transporter-1, ferroportin-1, and hephaestin, are yet to be fully understood in the vascular cells; therefore, whether expression of these genes are affected by Ang II in the vessel wall should be clarified in future studies.
In summary, long-term administration of Ang II induced the upregulation of ferritin and deposition of iron in the aortic wall. Iron chelation attenuated the induced increase in the expression of oxidative stress markers, HO-1 and 4-HNE-modified proteins, in the aortic wall, as well as Ang II-induced MCP-1 mRNA upregulation and impairment of vascular responsiveness to acetylcholine and exogenous form of nitric oxide induced by Ang II. Taken together, these data suggest that aberrant iron homeostasis may have a role in the Ang II-induced regulation of pro-atherogenic gene expression, vascular function, and vascular remodeling.
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Acknowledgments |
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This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (Grant 13671098), grants from Novartis Foundation for Gerontological Research, and that from Takeda Medical Research Foundation. We thank Kyoko Furuta, Kazuko Komatsumoto, and Naoko Amitani for their excellent technical assistance.
Received February 17, 2005; accepted July 25, 2005.
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