* Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan, ROC, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC
1 To whom correspondence should be addressed at the Institute of Biopharmaceutical Science, School of Life Sciences, National Yang-Ming University, Pei-Tou, Taipei, Taiwan 112. Fax: +(886)-2-28201886. E-mail: tclee{at}ym.edu.tw or bmtcl{at}ibms.sinica.edu.tw.
Received May 6, 2004; accepted January 25, 2005
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ABSTRACT |
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Key Words: sodium arsenite; heme oxygenase-1; monocyte chemoattractant protein-1; interleukin-6; oxidative stress; vascular smooth muscle cells.
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INTRODUCTION |
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When the blood vessel is injured, a variety of chemokines and growth factors are secreted by various cell types, including endothelial cells (ECs), platelets, immune cells, and vascular smooth muscle cells (VSMCs), and stimulate VSMCs to migrate into the intima layer and expand (Ross, 1999). The migration of VSMCs into the intima and their subsequent proliferation (intimal hyperplasia) is an early pathological process in atherosclerosis. Because of the involvement of a variety of cytokines, chemokines, and immune cells in the development of atherosclerotic lesions, chronic inflammation is suggested to be involved in the progression of atherosclerosis (Libby, 2002
).
The generation of reactive oxidants is a general manifestation of an inflammatory reaction. Various atherosclerosis-related factors, such as platelet-derived growth factor (PDGF), angiotensin II (Ang II), thrombin, and oxidized low-density lipoproteins, increase intracellular reactive oxidants or reactive oxygen species (ROS) production in VSMCs (Hsieh et al., 2001; Seshiah et al., 2002
; Sundaresan et al., 1995
) and stimulate VSMC proliferation (Gosgnach et al., 2000
; Griendling et al., 1994
; Sundaresan et al., 1995
). Mechanisms involved in enhanced VSMC proliferation by generation of ROS are mediated through activation of MAP kinases and Akt and their downstream transcription factors, such as NF-
B or AP-1, which are well-documented to regulate the expression of atherogenic related genes (Griendling et al., 2000
; Irani, 2000
). ROS are therefore implicated in the pathological processes of atherosclerosis (Ross, 1999
).
The generation of reactive oxidants during arsenic metabolism has been shown to play an important role in arsenic-induced injury (Gurr et al., 2003; Liu et al., 2001
). The involvement of reactive oxidants in iAs-induced DNA and chromosomal damage (Ho et al., 2000
; Lynn et al., 2000
), DNA repair inhibition (Mei et al., 2002
), and apoptosis (Nakagawa et al., 2002
) is well documented. Recent epidemiological studies have established a relationship between chronic arsenic exposure and increased levels of reactive oxidants in the blood of human populations drinking arsenic-contaminated water (Pi et al., 2002
; Wu et al., 2001
). ROS are therefore considered as a possible etiologic factor of atherogenicity (Wu et al., 2001
, 2003
).
In our previous study (Wu et al., 2003), the expression of several cytokine-related genes is increased in human subjects with increased arsenic exposure, including heme oxygenase-1 (HO-1), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6). Particularly, our study demonstrated an association for MCP-1 plasma protein level with blood arsenic in 65 study subjects of varying arsenic exposure level (Wu et al., 2003
). HO-1, a stress response gene with a cytoprotective and inflammation regulation function, MCP-1, a monocyte-recruiting chemokine, and IL-6, a pleiopotent inflammatory cytokine, are regulated by ROS and atherogenic factors and involved in modulating the biological functions of VSMCs (Browatzki et al., 2000
; Cushing et al., 1990
; Duckers et al., 2001
; Durante et al., 1999
; Morse and Choi, 2002
). Furthermore, the expression of these three genes has been detected in atherosclerotic lesion (Nelken et al., 1991
; Seino et al., 1994
; Wang et al., 1998
). These three genes are possibly involved in the development of atherosclerosis. Since VSMCs are a major cell type in vascular vessels, we therefore examined whether treatment with inorganic trivalent sodium arsenite (iAs, NaAsO2) resulted in the generation of ROS and subsequent enhancement of the expression of these three genes in VSMCs.
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MATERIALS AND METHODS |
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Measurement of mRNA levels by quantitative RT-PCR.
Total cellular RNA was extracted using the TRI-reagent according to the manufacturer's instructions (Molecular Research Center, Inc., Cincinnati, OH). The quantitative reverse transcriptase-polymerase chain reaction (quantitative RT-PCR) was used to analyze individual mRNA levels as described by Morrison et al. (1988). Each analysis was performed in triplicate. The relative mRNA levels for the genes of interest were calculated from the difference between the Ct value (number of cycles required to reach the detection threshold for the double-strand DNA product) for the gene of interest and that for an internal control gene, glyceraldehyde-3-phosphate dehydrogenase as described previously (Wu et al., 2003
). The Ct values were determined by using Sequence Detector System v1.7 software provided by the Applied Biosystems (Foster City, CA).
Measurement of protein levels.
Intracellular HO-1 protein levels were analyzed by Western blotting as described previously (Yih et al., 1997). In brief, rVSMCs or hVSMCs treated with iAs for different time periods were lysed, and the proteins were electrophoretically separated and transferred to a positively charged PVDF membrane. The PVDF membrane was immunoblotted with anti-HO-1 antibody or anti-actin antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). HO-1 protein and actin were visualized by the enhanced chemoluminescence method as described previously (Yih et al., 1997
). Levels of secreted MCP-1 and IL-6 in the culture medium from iAs-treated VSMCs were determined using enzyme-linked immunosorbent assay (ELISA) kits (Amersham Pharmacia Biotech, Uppsala, Sweden) according to the manufacturer's instructions.
Determination of ROS production.
2',7'-dichlorofluorescein diacetate (DCF-DA) was used to measure ROS production in VSMCs (Huang et al., 1993). In brief, proliferating rVSMCs were treated with iAs for various time periods, DCF-DA (at a final concentration of 20 µM) being added to the culture medium 30 min before the end of iAs treatment. The rVSMCs were then trypsinized and resuspended in Hank's balanced salt solution. The fluorescence of the DCF formed by oxidation of DCF-DA by cellular oxidants was measured using a flow cytometer with an excitation wavelength of 488 nm and an emission wavelength of 525 nm.
Survival assay.
To determine the protective effects of HO-1 on iAs-induced cell injury, the proliferation rates of VSMCs were measured by counting the cell number after treatment with iAs or iAs plus SnPP. In brief, 3 x 104 rVSMCs were seeded onto a 60 mm dish and cultivated for 24 h. The cells were then treated with various concentrations of iAs (0, 1, 2, 5 µM) with vehicle (0.25% DMSO) or 50 µM SnPP (dissolved in DMSO) for 24 h. Afterward, the media were replaced with fresh medium without drugs. After further cultivating for 72 h, the cells were trypsinized and counted with a cell counter (hematology analyzer, EXCELL 300, Metertech).
Chemotaxis assay.
MCP-1-induced monocyte chemotaxis was measured using 12-well Transwell polystyrene trays (Corning Costar Corp., Cambridge, MA) and a 5 µm pore polycarbonate membrane (McQuibban et al., 2002). Conditioned medium from resting hVSMCs incubated with or without 5 µM iAs was harvested and a 600 µl aliquot loaded into the lower chamber, while 100 µl of the human monocytic leukemia cell line, THP-1, at a density of 5 x 106 cells/ml in HAM's F-12K medium containing 0.1% FBS were loaded into the upper chamber. After incubation in a 37°C incubator for 2 h, the THP-1 cells on the lower chamber-side of the membrane were fixed with methanol, stained with DAPI. In each treatment, the average cell number of three randomly selected fields (using 10x eyepieces and 40x objective) was scored under a fluorescence microscopy. In control group, 100 to 140 migrating cells were obtained in each field. The relative migration index was calculated by dividing the number of THP-1 cells that migrated in response to conditioned medium from iAs-treated cultures by the number that migrated in response to conditioned medium from untreated controls supplemented with 5 µM iAs prior to assay. Pilot studies showed that addition of 5 µM iAs to conditioned medium from untreated cultures did not affect the migration index of THP-1 cells. To confirm the observed chemotaxis was due to secreted MCP-1, anti-human MCP-1 antibody (R&D Systems, Inc., Minneapolis, MN) at a final concentration of 0.83 µg/ml was added to the conditioned medium in the lower chamber 10 min before loading the cells into the upper chamber.
Treatment with ROS modulators.
Catalase (CAT) was added to the culture medium for 4 h. To avoid the interference with iAs, the medium was replaced with fresh medium before treatment with iAs (5 µM for 4 h). Superoxide dismutase (SOD) was added to the culture medium 4 h before iAs treatment, while allopurinol (AP), dimethylsulfoxide (DMSO), and L--nitro-L-arginine (L-NNA) were added 30 min before iAs treatment; these reagents were then left in the medium during the subsequent iAs treatment (5 µM for 4 h).
Statistical analysis.
The results are expressed as the mean ± SD. Statistical analyses were performed using Student's two-tailed unpaired t-test. p values < 0.05 were considered statistically significant.
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RESULTS |
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DISCUSSION |
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Several reports have shown that iAs treatment results in increased ROS and NO production in a variety of cells in culture (Barchowsky et al., 1999; Lee and Ho, 1995
; Lynn et al., 2000
), and in the blood of human populations drinking arsenic-contaminated water (Pi et al., 2002
; Wu et al., 2001
). Precisely how iAs results in an increase in ROS/NO is unclear. However, iAs is reported to increase superoxide anion production by stimulating NADH oxidase in hVSMCs and porcine aortic endothelial cells (Lynn et al., 2000
; Smith et al., 2001
). Alternatively, iAs may interact with sulfhydryl groups of biomolecules and GSH, resulting in a decreased capacity for scavenging ROS (Nakagawa et al., 2002
; Wang et al., 1996
). Downregulation of antioxidant enzymes, such as phospholipid hydroperoxide glutathione peroxidase, is another mechanism for increasing intracellular peroxide levels (Huang et al., 2002
). The cellular signaling cascade activated by iAs-induced oxidative stress has been reviewed. Emerging evidence has shown that iAs-induced oxidative stress could activate MAP kinases, such as JNK and p38 kinase, and subsequently activate their downstream transcription factors, AP-1 and NF-
B (Bernstam and Nriagu, 2000
; Qian et al., 2003
). In this study, we demonstrated that iAs-treatment resulted in increasing intracellular ROS production in VSMCs. Thus iAs is likely through similar signaling pathway to stimulate the expression of HO-1, MCP-1, and IL-6.
MCP-1, a C-C family chemokine, is expressed in endothelial cells, foam cells, and VSMCs of atherosclerotic lesions (Nelken et al., 1991), and has strong chemotactic activity for immune cells, such as monocytes (Rollins, 1997
). The recruitment of circulating monocytes is a crucial step in the initiation of atherosclerosis (Ross, 1993
). Numerous reports have shown that MCP-1 is induced in VSMCs by a variety of stimuli, including Ang II (Funakoshi et al., 2001
), thrombin (Wenzel et al., 1995
), uric acid (Kanellis et al., 2003
), Fas ligand plus cycloheximide (Schaub et al., 2000
), and activated platelets (Massberg et al., 2003
). Expression of MCP-1 may result in the accumulation of inflammatory cells, such as macrophages, in atherosclerotic lesions. Our results showed that the enhanced chemotactic activity for human monocytes seen in conditioned medium from iAs-treated VSMCs could be suppressed by antibody against MCP-1. Since VSMCs are the major cell type in the media of arteries, MCP-1 released from VSMCs by iAs treatment may be involved in the recruitment of circulating monocytes and thus in initiating atherogenesis. Our current results also support our previous finding that plasma levels of MCP-1 show a good correlation with blood arsenic levels in human populations exposed to arsenic in drinking water (Wu et al., 2003
).
IL-6, a proinflammatory cytokine and a major inducer of C-reactive protein (CRP) (Heinrich et al., 1990), is also present in atherosclerotic lesions (Seino et al., 1994
). Both IL-6 and CRP are considered as strong risk markers of cardiovascular diseases (Blake and Ridker, 2001
). Several vasoactive substances, such as PDGF, Ang II, thrombin, and endothelin, are reported to induce IL-6 expression in VSMCs (Browatzki et al., 2000
; Funakoshi et al., 1999
; Roth et al., 1995
; Tokunou et al., 2001
). It has been reported that IL-6 at levels of ng/ml range could stimulate VSMCs proliferation and migration (Ikeda et al., 1991
; Liu et al., 2004
), which are important manifestation of atherogenesis. Since the concentrations of secreted IL-6 in medium of iAs-treated cultures were ranged at pg/ml levels, anti-IL-6 antibody was unable to inhibit the proliferation or migration ability in iAs-treated rVSMCs (data not shown). This result may be explained not only by the low level of IL-6 secretion but also the presence of other mitogens or migration factors in culture medium of rVSMC. IL-6 also stimulates the expression of adhesion molecules and increases cell-cell permeability in ECs (Maruo et al., 1992
; Watson et al., 1996
). Increased levels of adhesion molecules and increased ECs permeability could promote the attachment and penetration of circulating immune cells, such as monocytes. Although the exact physiological role of iAs-induced IL-6 in VSMCs still requires further investigation, the enhanced expression of IL-6 seen in iAs-treated VSMCs may act as a risk factor of iAs-induced cardiovascular disorders.
In addition to cytokines and chemokines, the heme degradation enzyme, HO-1, is also expressed in atherosclerotic lesions (Wang et al., 1998). The products of heme degradation are iron, carbon monoxide, and biliverdin. Carbon monoxide acts as a vasodilator (Duckers et al., 2001
), while bilirubin, produced by reduction of biliverdin, is a potent antioxidant (Stocker et al., 1987
). Because of this, HO-1 has been proposed to have roles in cytoprotection and in the regulation of inflammation (Morse and Choi, 2002
). In this study, SnPP, a competitive inhibitor of HO-1, was shown to significantly reduce cell survival of proliferating rVSMCs, indicating that iAs-induced HO-1 plays a cytoprotective role in iAs-damaged VSMCs. In fact, the growth promoting properties of HO-1 have been demonstrated in many cell types and in transgenic animal models and humans (Durante, 2003
). Recently, HO-1 was further reported to play an important role in angiogenesis (Bussolati et al., 2004
). Therefore, the roles of HO-1 on atherogenesis require further clarification.
Since arsenic is a well-documented potent inducer of HO-1 in many cell types (Lee and Ho, 1995; Taketani et al., 1989
), HO-1 is also considered as a good marker of exposure to arsenic and oxidative stress. In the present study, iAs treatment of HFW resulted in increased HO-1 gene expression, but suppression of MCP-1 and IL-6 expression. This finding is consistent with the results of our previous study using cDNA microarrays to study the effect of iAs treatment on the gene expression profile of HFW cells (Yih et al., 2002
). Inhibition of IL-6 expression by iAs is also observed in human intestinal epithelial cells (Hershko et al., 2002
). These results indicated that although HO-1, MCP-1, and IL-6 are oxidative response genes, their response to iAs-enhanced oxidative stress is cell type dependent. The cell type specificity of the induction of MCP-1 and IL-6 requires further study.
Our present study provides evidence that exposure to iAs increases the generation of ROS/NO and thus enhances the expression of the HO-1, MCP-1, and IL-6 genes in VSMCs. Expression of MCP-1 and IL-6 may promote the initiation of atherogenesis by increasing the attachment, penetration, and migration of monocytes. These three gene products are also involved in regulation of VSMC proliferation. The findings presented here suggest a possible mechanism for atherogenesis in arsenic-exposed humans. A better understanding of the atherogenic mechanisms of arsenic should provide the basis for improved interventional approaches for both treatment and prevention.
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ACKNOWLEDGMENTS |
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REFERENCES |
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---|
Blake, G. J., and Ridker, P. M. (2001). Novel clinical markers of vascular wall inflammation. Circ. Res. 89, 763771.
Bernstam, L., and Nriagu, J. (2000). Molecular aspects of arsenic stress. J. Toxicol. Environ. Health B. 3, 293322[CrossRef][ISI]
Browatzki, M., Schmidt, J., Kubler, W., and Kranzhofer, R. (2000). Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. Basic Res. Cardiol. 95, 98105.[CrossRef][Medline]
Bussolati, B., Ahmed, A., Pemberton, H., Landis, R. C., Di Carlo, F., Haskard, D. O., and Mason, J. C. (2004). Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: Induction of angiogenesis and inhibition of leukocytic infiltration. Blood 103, 761766.
Chen, C. J., Chen, C. W., Wu, M. M., and Kuo, T. L. (1992). Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br. J. Cancer 66, 888892.[ISI][Medline]
Chen, C.-J., Hsueh, Y.-M., Lai, M.-S., Shyu, M.-P., Chen, S.-Y., Wu, M.-M., Kuo, T.-L., and Tai, T.-Y. (1995). Increased prevalence of hypertension and long-term arsenic exposure. Hypertension 25, 5360.
Chiou, H.-Y., Huang, W.-I., Su, C.-L., Chang, S.-F., Hsu, Y.-H., and Chen, C.-J. (1997). Dose-response relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28, 17171723.
Cushing, S. D., Berliner, J. A., Valente, A. J., Territo, M. C., Navab, M., Parhami, F., Gerrity, R., Schwartz, C. J., and Fogelman, A. M. (1990). Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. U.S.A. 87, 51345138.
Duckers, H., Boehm, M., True, A. L., Yet, S.-F., San, H., Park, J. L., Webb, R. C., Lee, M.-E., Nabel, G. J., and Nabel, E. G. (2001). Heme oxygenase-1 protects against vascular constriction and proliferation. Nature Med. 7, 693698.[CrossRef][ISI][Medline]
Durante, W. (2003). Heme oxygenase-1 in growth control and its clinical application to vascular disease. J. Cell. Physiol. 195, 373382.[CrossRef][ISI][Medline]
Durante, W., Peyton, K. J., and Schafer, A. I. (1999). Platelet-derived growth factor stimulates heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 19, 26662672.
Foresti, R., Clark, J. E., Green, C. J., and Motterlini, R. (1997). Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J. Biol. Chem. 272, 1841118417.
Foresti, R., Goatly, H., Green, C. J., and Motterlini, R. (2001). Role of heme oxygenase-1 in hypoxia-reoxygenation: Requirement of substrate heme to promote cardioprotection. Am. J. Physiol. Heart Circ. Physiol. 281, H1976H1984.
Funakoshi, Y., Ichiki, T., Ito, K., and Takeshita, A. (1999). Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. Hypertension 34, 118125.
Funakoshi, Y., Ichiki, T., Shimokawa, H., Egashira, K., Takeda, K., Kaibuchi, K., Takeya, M., Yoshimura, T., and Takeshita, A. (2001). Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension 38, 100104.
Gosgnach, W., Messika-Zeitoun, D., Gonzalez, W., Philipe, M., and Michel, J. B. (2000). Shear stress induces iNOS expression in cultured smooth muscle cells: Role of oxidative stress. Am. J. Physiol.-Cell Physiol. 279, C1880C1888.
Griendling, K. K., Minieri, C. A., Ollerenshaw, J. D., and Alexander, R. W. (1994). Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ. Res. 74, 11411148.[Abstract]
Griendling, K. K., Sorescu, D., Lassegue, B., Masuko, U. F. (2000). Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler. Thromb. Vasc. Biol. 20, 21752183.
Gurr, J. R., Yih, L. H., Samikkannu, T., Bau, D. T., Lin, S. Y., and Jan, K. Y. (2003). Nitric oxide production by arsenite. Mutat. Res. 533, 173182.[Medline]
Heinrich, P. C., Castell, J. V., and Andus, T. (1990). Interleukin-6 and the acute phase response. Biochem. J. 265, 621636.[ISI][Medline]
Hershko, D. D., Robb, B. W., Hungeness, E. S., Luo, G., Guo, X., and Hasselgren, P. (2002). Arsenite inhibits interleukin-6 production in human intestinal epithelial cells by down-regulating nuclear factor-B activity. Clin. Sci. 103, 381390.[ISI][Medline]
Ho, I. C., Yih, L. H., Kao, C.-Y., and Lee, T. C. (2000). Tin-protoporphyrin potentiates arsenite-induced DNA strand breaks, chromatid breaks, and kinetochore-negative micronuclei in human fibroblasts. Mutat. Res. 452, 4150.[ISI][Medline]
Hsieh, C. C., Yen, M. H., Yen, C. H., and Lau, Y. T. (2001). Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovascular Res. 49, 135145.[CrossRef][ISI][Medline]
Hsueh, Y. M., Wu, W. L., Huang, Y. L., Chiou, H. Y., Tseng, C. H., and Chen, C. J. (1998). Low serum carotene level and increased risk of ischemic heart disease related to long-term arsenic exposure. Atheriosclerosis 141, 249257.[CrossRef]
Huang, H.-S., Chang, W. C., and Chen, C. J. (2002). Involvement of reactive oxygen species in arsenite-induced downregulation of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells. Free Rad. Biol. Med. 33, 864873.[CrossRef][ISI][Medline]
Huang, X., Frenkel, K., Klein, C. B., and Costa, M. (1993). Nickel induces increased oxidants in intact cultured mammalian cells as detected by dichlorofluorescein fluorescence. Toxicol. Appl. Pharmacol. 120, 2936.[CrossRef][ISI][Medline]
IARC (1987). Some metals and metallic compounds. In IARC Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans (W. IARC, Ed.), Vol. 23, pp. 39142. IARC, Lyon, France.
Ikeda, U., Ikeda, M., Oohara, T., Oguchi, A., Kamitani, T., Tsuruya, Y., and Kano, S. (1991). Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am. J. Physiol. 260, H17131717.[ISI][Medline]
Irani, K. (2000). Oxidant signaling in vascular cell growth, death, and survival. Circ. Res. 87, 179183.
Kanellis, J., Watanabe, S., Li, J. H., Kang, D. H., Li, P., Nakagawa, T., Wamsley, A., Sheikh-Hamad, D., Lan, H. Y., Feng, L., and Johnson, R. J. (2003). Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 41, 12871293.
Lee, T.-C., and Ho, I.-C. (1995). Modulation of cellular antioxidant defense activities by sodium arsenite in human fibroblasts. Arch. Toxicol. 69, 498504.[CrossRef][ISI][Medline]
Libby, P. (2002). Inflammation in atherosclerosis. Nature 420, 868874.[CrossRef][ISI][Medline]
Liu, S. X., Athar, M., Lippai, I., Waldren, C., and Hei, T. K. (2001). Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity. Proc. Natl. Acad. Sci. U.S.A. 98, 16431648.
Lynn, S., Gurr, J.-R., Lai, H.-T., and Jan, K. Y. (2000). NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. Circ. Res. 86, 514519.
Liu, Z., Dronadula, N., and Rao, G. N. (2004). A novel role for nuclear factor of activated T cells in receptor tyrosine kinase and G protein-coupled receptor agonist-induced vascular smooth muscle cell motility. J. Biol. Chem. 279, 4121841226.
Maruo, N., Morita, I., Shirao, M., and Murota, S. (1992). IL-6 increases endothelial permeability in vitro. Endocrinology 131, 710714.[Abstract]
Massberg, S., Vogt, F., Dickfeld, T., Brand, K., Page, S., and Gawaz, M. (2003). Activated platelets trigger an inflammatory response and enhance migration of aortic smooth muscle cells. Thromb. Res. 110, 187194.[CrossRef][ISI][Medline]
McQuibban, G. A., Gong, J.-H., Wong, J. P., Wallace, J. L., Clark-Lewis, I., and Overall, C. M. (2002). Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100, 11601167.
Mei, N., Kunugita, N., Hirano, T., and Kasai, H. (2002). Acute arsenite-induced 8-hydorxyguanine is associated with inhibition of repair activity in cultured human cells. Biochem. Biophys. Res. Commun. 297, 924930.[CrossRef][ISI][Medline]
Morrison, T. B., Weis, J. J., and Wittwer, C. T. (1988). Quantitation of low-copy transcripts by continuous SYBR Green I monitoring during amplification. BioTechniques 24, 954958, 960, 962.
Morse, D., and Choi, A. M. (2002). Heme oxygenase-1: The "emerging molecule" has arrived. Am. J. Respir. Cell Mol. Biol. 27, 816.
Nakagawa, Y., Akao, Y., Morikawa, H., Hirata, I., Katsu, K., Naeo, T., Ohishi, N., and Yagi, K. (2002). Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. Life Sci. 70, 22532269.[CrossRef][ISI][Medline]
Nelken, N. A., Coughlin, S. R., Gordon, D., and Wilcox, J. N. (1991). Monocyte chemoattractant protein-1 in human atheromatous plaques. J. Clin. Invest. 88, 11211127.[ISI][Medline]
Pi, J., Qu, W., Reece, J. M., Kumagai, Y., and Waalkes, M. P. (2003). Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: Involvement of hydrogen peroxide. Exp. Cell Res. 290, 234245.[CrossRef][ISI][Medline]
Pi, J., Yamauchi, H., Kumagai, Y., Sun, G., Yoshida, T., Aikawa, H., Hopenhayn-Rich, C., and Shimojo, N. (2002). Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water. Environ. Health Perspect. 110, 331336.[ISI][Medline]
Qian, Y., Castranova, V., and Shi, X. (2003). New perspectives in arsenic-induced cell signal transduction. J. Inorg. Biochem. 96, 271278[CrossRef][ISI][Medline]
Rahman, M., Tondel, M., Ahmad, S. A., and Axelson, O. (1998). Diabetes mellitus associated with arsenic exposure in Bangladesh. Am. J. Epidemiol. 148, 198203.[Abstract]
Rahman, M., Tondel, M., Ahmad, S. A., Chowdhury, I. A., Faruquee, M. H., and Axelson, O. (1999). Hypertension and arsenic exposure in Bangladesh. Hypertension 33, 7478.
Rollins, B. J. (1997). Chemokines. Blood 90, 909928.
Ross, R. (1999). Atherosclerosisan inflammatory disease. N. Engl. J. Med. 340, 115126.
Ross, R. E. (1993). Rous-Whipple Award Lecture: Atherosclerosis: A defense mechanism gone awry. Am. J. Pathol. 143, 9871002 .[ISI][Medline]
Roth, M., Nauck, M., Tamm, M., Perruchoud, A. P., Ziesche, R., and Block, L. H. (1995). Intracellular interleukin 6 mediates platelet-derived growth factor-induced proliferation of nontransformed cells. Proc. Natl. Acad. Sci. U.S.A. 92, 13121316.
Schaub, F. J., Han, D. K. M., Conrad Liles, W., Adams, L. D., Coats, S. A., Ramachandran, R. K., Seifert, R. A., Schwartz, S. M., and Bowen-Pope, D. F. (2000). Fas/FADD-mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells. Nature Med. 6, 790796.[CrossRef][ISI][Medline]
Seino, Y., Ikeda, U., Ikeda, M., Yamamoto, K., Misawa, Y., Hasegawa, T., Kano, S., and Shimadam, K. (1994). Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 6, 8791.[CrossRef][ISI][Medline]
Seshiah, P. N., Weber, D. S., Rocic, P., Valppu, L., Taniyama, Y., and Griendling, K. K. (2002). Angiotensin II stimulation of NAD(P)H oxidase activity: Upstream mediators. Circ. Res. 91, 406413.
Sheehy, J. W., and Jones, J. H. (1993). Assessment of arsenic exposures and controls in gallium arsenide production. Am. Ind. Hyg. Assoc. J. 53, 6169.
Smith, K. R., Klei, L. R., and Barchowsky, A. (2001). Arsenite stimulates plasma membrane NADPH oxidase in vascular endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L442L449.
Stocker, R., Yamamoto, Y., McDonagh, A. F., Glazer, A. N., and Ames, B. N. (1987). Bilirubin is an antioxidant of possible physiological importance. Science 235, 10431046.[ISI][Medline]
Sundaresan, M., Yu, Z.-X., Ferrans, V. J., Irani, K., and Finkel, T. (1995). Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296299.[Abstract]
Taketani, S., Kohno, H., Yoshinaga, T., and Tokunaga, R. (1989). The human 32-kDa stress protein induced by exposure to arsenite and cadmium ions is heme oxygenase. FEBS Lett. 245, 173176.[CrossRef][ISI][Medline]
Tokunou, T., Ichiki, T., Takeda, K., Funakoshi, Y., Iino, N., Shimokawa, H., Egashira, K., and Takeshita, A. (2001). Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 21, 17591763.
Tseng, C. H., Tai, T. Y., Chong, C. K., Tseng, C. P., Lai, M. S., Lin, B. J., Chiou, H. Y., Hsueh, Y. M., Hsu, K. H., and Chen, C. J. (2000). Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: A cohort study in arseniasis-hyperendemic villages in Taiwan. Environ. Health Perspect. 108, 847851.[ISI][Medline]
Wang, C. H., Jeng, J. S., Yip, P. K., Chen, C. L., Hsu, L. I., Hsueh, Y. M., Chiou, H. Y., Wu, M. M., and Chen, C. J. (2002). Biological gradient between long-term arsenic exposure and carotid atherosclerosis. Circulation 105, 18041809.
Wang, L.-J., Lee, T.-S., Lee, F.-Y., Pai, R.-C., and Chau, L.-Y. (1998). Expression of heme-oxygenase-1 in atherosclerotic lesions. Am. J. Pathol. 152, 711720.[Abstract]
Wang, T.-S., Kuo, C.-F., Jan, K. Y., and Huang, H. (1996). Arsenite induces apoptosis in Chinese hamster ovary cells by generation of reactive oxygen species. J. Cell. Physiol. 169, 256268.[CrossRef][ISI][Medline]
Watson, C., Whittaker, S., Smith, N., Vora, A. J., Dumonde, D. C., and Brown, K. A. (1996). IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes. Clin. Exp. Immunol. 105, 112119.[CrossRef][ISI][Medline]
Wenzel, U. O., Fouqueray, B., Grandaliano, G., Kim, Y. S., Karamitsos, C., Valente, A. J., and Abboud, H. E. (1995). Thrombin regulates expression of monocyte chemoattractant protein-1 in vascular smooth muscle cells. Circ. Res. 77, 503509.
Wu, M. M., Chiou, H. Y., Ho, I. C., Chen, C. J., and Lee, T. C. (2003). Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects. Environ. Health Perspect. 111, 14291438.[ISI][Medline]
Wu, M.-M., Chiou, H.-Y., Wang, T.-W., Hsueh, Y.-M., Wang, I.-H., Chen, C.-J., and Lee, T.-C. (2001). Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan. Environ. Health Perspect. 109, 10111017.[ISI][Medline]
Yih, L.-H., Ho, I.-C., and Lee, T.-C. (1997). Sodium arsenite disturbs mitosis and induces chromosome loss in human fibroblasts. Cancer Res. 57, 50515059.[Abstract]
Yih, L. H., and Lee, T. C. (2000). Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res. 60, 63466352.
Yih, L. H., Peck, K., and Lee, T. C. (2002). Changes in gene expression profiles of human fibroblasts in response to sodium arsenite. Carcinogenesis 60, 63466352.
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