Fluid Shear Stress Transcriptionally Induces Lectin-like Oxidized LDL Receptor-1 in Vascular Endothelial Cells

From the Departments of Geriatric Medicine and Pharmacology (T.M., N.K., T.S., T.M., T.K.), Graduate School of Medicine, Kyoto University, Kyoto, Japan, and the Department of Biomedical Engineering (R.K., J.A.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan. The present address for Dr Murase is Biological Science Laboratories, Kao Corp, Ichikaimachi, Tochigi, Japan.

Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail nkume{at}kuhp.kyoto-u.ac.jp

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Abstract—Fluid shear stress has been shown to modulate various endothelial functions, including gene expression. In this study, we examined the effect of fluid shear stress on the expression of lectin-like oxidized LDL receptor-1 (LOX-1), a novel receptor for atherogenic oxidized LDL in cultured bovine aortic endothelial cells (BAECs). Exposure of BAECs to the physiological range of shear stress (1 to 15 dyne/cm²) upregulated LOX-1 protein and mRNA in a time-dependent fashion. LOX-1 mRNA levels peaked at 4 hours, and LOX-1 protein levels peaked at 8 hours. Inhibition of de novo RNA synthesis by actinomycin D totally abolished shear stress–induced LOX-1 mRNA expression. Furthermore, nuclear runoff assay showed that shear stress directly stimulates transcription of the LOX-1 gene. Chelation of intracellular Ca²⁺ with quin 2-AM completely reduced shear stress–induced LOX-1 mRNA expression; furthermore, the treatment of BAECs with ionomycin upregulated LOX-1 mRNA levels in a dose-dependent manner. Taken together, physiological levels of fluid shear stress can regulate LOX-1 expression by a mechanism dependent on intracellular Ca²⁺ mobilization. Inducible expression of LOX-1 by fluid mechanics may play a role in localized expression of LOX-1 and atherosclerotic lesion formation in vivo.

Key Words: atherosclerosis • oxidized LDL • fluid shear stress • intracellular Ca²⁺ • C-type lectin

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Endothelial cells lining the inner surface of vessel walls are in direct contact with blood flow, which generates a hemodynamic shear stress acting on the apical surface of vascular endothelium.^{1 2} Fluid shear stress has been shown to modulate a variety of endothelial functions, including the expression of a variety of genes, such as endothelin-1,^{3 4 5} cyclooxygenase-2,⁶ NO synthase,^{6 7} tissue factor,⁸ transforming growth factor-ß,⁹ platelet-derived growth factor (PDGF),^{10 11} basic fibroblast growth factor,¹¹ heparin-binding epidermal growth factor–like growth factor,¹² monocyte chemotactic protein-1,¹³ intercellular adhesion molecule-1,^{14 15} and vascular cell adhesion molecule-1,^{16 17} as well as its effects on cytoskeletal organization and cell morphology.^{4 18 19} These biological effects elicited by fluid shear stress appear to be mediated by intracellular signal transduction cascades, including intracellular Ca²⁺ mobilization,^{20 21 22} inositol trisphosphate,²³ K⁺ channel,²⁴ G protein,²⁵ mitogen-activated protein kinases,^{26 27} N-terminal Jun kinase,^{28 29} and platelet endothelial cell adhesion molecule-1 tyrosine phosphorylation,³⁰ and by the subsequent activation of transcription factors, such as activator protein-1 (AP-1),^{31 32} nuclear factor-B (NF-B),^{31 33} and Egr-1 (an early growth response gene product),^{34 35} and may potentially affect vascular tone, thrombus formation, and atherogenesis.^{1 36}

On the other hand, oxidatively modified LDL (Ox-LDL) has been suggested to play key roles in atherogenesis. In particular, modulation of endothelial functions elicited by Ox-LDL and its lipid constituents has been implicated in the initiation of this complex disease process.^{36 37} We have recently identified a novel endothelial receptor for Ox-LDL, designated lectin-like Ox-LDL receptor-1 (LOX-1), whose structure belongs to the C-type lectin family.³⁸ LOX-1 is expressed in vascular endothelium in vivo in arterial and aortic endothelial cells, including atherosclerotic lesions.³⁸ Functional analysis revealed that LOX-1 expressed on the surface of endothelial cells supports binding, internalization, and proteolytic degradation of Ox-LDL. With regard to transcriptional regulation of LOX-1, an inflammatory stimulus, such as tumor necrosis factor-, appears to stimulate transcription of the LOX-1 gene.^38A LOX-1 expression in vivo also has been shown to be upregulated in the aortas and veins of hypertensive rats.³⁹ Therefore, we have tested the hypothesis that expression of LOX-1 can be modulated by fluid mechanical stimuli in vascular endothelial cells.

In the present study, we provide evidence that fluid shear stress is a potent stimulus to transcriptionally induce the expression of LOX-1 in cultured bovine aortic endothelial cells (BAECs).

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Reagents
DMEM was obtained from Nissui. FCS was obtained from Boehringer Mannheim. [³²P]UTP, the Gene Image DNA labeling and detection system, ECL Western blotting detection reagents, and Hybond-N+ membranes were obtained from Amersham. Quin 2-AM, Isogen, and Isogen-LS were from Wako Pure Chemical. PVDF transfer membranes were obtained from Millipore.

Cell Culture
BAECs were isolated by scraping the inner surface of bovine aortas with a glass coverslip and cultured in DMEM containing 10% heat-inactivated FCS in an atmosphere of 95% air/5% CO₂ at 37°C as previously described.³⁸ For shear experiments, BAECs were seeded on collagen-coated glass slides (70x100 mm) in DMEM with 10% FCS. Before experiments, BAECs on the glass slides were incubated with serum-free DMEM for 24 hours.

Shear Stress Apparatus
A parallel-plate type of flow chamber was used to produce laminar flow as previously described.^{15 16 17 20} In brief, BAECs were cultured on glass plates and loaded into a rectangular parallel-plate flow chamber. Shear stress was increased suddenly from 0 (static) to 15 dyne/cm² (or the indicated intensities of shear stress) and was maintained at the same level for the time periods indicated for each experiment. Culture media were recirculated into the chamber and kept at a constant temperature of 37°C with a gas mixture of 95% air/5% CO₂.

Northern Blot Analysis
BAECs were washed in PBS, and total RNA was isolated using Isogen. Equal amounts (10 µg) of total RNA were subjected to electrophoresis through 1% agarose/formamide gels and blotted onto Hybond-N+ membranes. Hybridization and detection were performed by fluorescein-labeled cDNA using the Gene Image random prime labeling and detection system (Amersham) according to the manufacturer's instructions. In brief, the blots were prehybridized for 6 hours at 65°C in a solution containing 5% (wt/vol) dextran sulfate, 5x SSC, 0.1% (wt/vol) SDS, and blocking reagent and subsequently hybridized with a fluorescein-labeled cDNA probe at 65°C overnight. The membranes were washed with 1x SSC and 0.1% (wt/vol) SDS for 15 minutes and then washed with 0.1x SSC and 0.1% (wt/vol) SDS for 15 minutes at 65°C. After nonspecific binding of antibodies was blocked, the membranes were incubated with alkaline phosphatase–labeled anti-fluorescein antibody for 1 hour and then detected by chemiluminescence (CDP-star reagent, Amersham). Densitometric scanning was performed to quantify the amounts of mRNA using NIH Image. Amounts of LOX-1 mRNA were normalized with the amounts of GAPDH mRNA.

Western Blot Analysis
BAECs were washed in PBS and lysed in buffer containing 62.5 mmol/L Tris-HCl, 2% (wt/vol) SDS, and 10% (vol/vol) glycerol. Equal protein concentrations of the lysates were subjected to SDS-polyacrylamide (10%) gel electrophoresis, followed by electroblotting onto an Immobilon PVDF transfer membrane. Determination of protein concentrations was carried out by the method of Lowry. Blotted membranes were probed with a mouse monoclonal antibody directed to bovine LOX-1,³⁸ incubated with horseradish peroxidase–labeled-anti-mouse immunoglobulin for 1 hour, washed with PBS containing 0.1% (vol/vol) Tween 20, and then detected by ECL Western blotting detection reagents. Densitometric scanning was performed to quantify the amounts of LOX-1 protein using NIH Image.

Nuclear Runoff Assay
Nuclear runoff assay was performed as previously described,⁴⁰ with minor modification. Briefly, the cells were washed with ice-cold PBS and lysed with 0.5% Nonidet P-40 solution (10 mmol/L Tris-HCl, 10 mmol/L NaCl, 3 mmol/L MgCl₂, and 0.5% NP-40 [vol/vol], pH 7.4). The nuclei were isolated by centrifugation and resuspended in a 40% glycerol buffer (50 mmol/L Tris-HCl, 40% [vol/vol] glycerol, 5 mmol/L MgCl₂, and 0.1 mmol/L EDTA, pH 8.3). Nascent transcription in vitro was performed with [³²P]UTP and other unlabeled nucleotides at 30°C for 30 minutes. Transcribed RNA was isolated by Isogen-LS, followed by denaturation with sodium hydroxide and ethanol precipitation. Linearized target cDNAs (5 µg in plasmid form) were alkali-denatured and immobilized onto Hybond-N+ membranes using a slot blot apparatus (Schleicher & Shuell Inc). The membranes were hybridized with transcribed RNAs containing an equal amount of radioactivity in a solution containing 50% (vol/vol) formamide, 5x SSPE (1x SSPE consists of 0.15 mol/L NaCl, 10 mmol/L NaH₂PO₃, and 1 mmol/L EDTA, pH 7.4), 0.1% (wt/vol) SDS, 10% (vol/vol) Denhardt's solution, and denatured salmon sperm DNA at 42°C for 36 hours. Filters were washed in 1x SSC with 0.1% (wt/vol) SDS for 15 minutes at room temperature, washed with 0.2x SSC supplemented with 0.1% (wt/vol) SDS for 10 minutes at 42°C, and then autoradiographed with Fujix Bioimage Analyzer BAS2000 (Fuji Photo Film).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Shear Stress Induces LOX-1 Expression in Cultured Endothelial Cells
To test whether shear stress induces LOX-1 expression at the protein level, confluent BAECs in a flow chamber were subjected to a steady level of laminar shear stress of 15 dyne/cm² for various periods of time. Time course of shear stress–induced LOX-1 protein expression showed that elevated levels of LOX-1 protein were detectable within 4 hours and reached to the maximal level at 8 hours in response to 15 dyne/cm² of shear stress (Figure 1A). Densitometric analysis showed that exposure to shear stress resulted in 2.4-fold, 3.7-fold, and 2.9-fold increases in the amounts of LOX-1 protein at 4, 8, and 12 hours, respectively, compared with the levels in BAECs kept in a static condition. To determine whether shear stress–induced expression of LOX-1 depends on increased expression of LOX-1 mRNA, Northern blot analyses were performed. As shown in Figure 1B, confluent BAECs constitutively expressed modest levels of LOX-1 mRNA. Exposure of BAECs to 15 dyne/cm² of shear stress led to a rapid and transient increase in the amount of LOX-1 mRNA. The LOX-1 mRNA levels peaked at 4 hours (5.6-fold increase) and were reduced after 8 hours.

View larger version (28K): [in this window] [in a new window]   Figure 1. Time course of shear stress–induced LOX-1 expression. After BAECs cultured on glass slides were exposed to shear stress (15 dyne/cm2) for the indicated time periods, immunoblot (A) and Northern blot (B) analyses were performed to measure LOX-1 protein and mRNA levels. BAECs kept in a static condition served as "time 0." One of 2 independent experiments is shown.

To examine shear-force dependence in LOX-1 expression, confluent BAECs were exposed to a broad range of shear stresses (1 to 15 dyne/cm²) for 8 hours. These levels of shear stress appear to be within the physiological range of shear stress in vivo and have been shown to regulate a variety of endothelial genes in vitro. As shown in Figure 2A and 2B, shear stress force-dependently induced the expression of LOX-1 protein; increased amounts of LOX-1 protein were detectable in BAECs exposed to shear stress as low as 1 to 2 dyne/cm². Elevated levels of LOX-1 mRNA were observed in BAECs stimulated with shear stress as low as 2 dyne/cm² (Figure 2C).

View larger version (37K): [in this window] [in a new window]   Figure 2. Dependence on intensities of shear stress in LOX-1 expression. After BAECs were exposed to shear stresses of 1 to 5 dyne/cm2 (A) or 2 to 15 dyne/cm2 (B and C), LOX-1 protein and mRNA levels were evaluated by immunoblot analyses (A and B) and Northern blot analyses (C). A representative figure from 2 independent experiments is shown.

To explore whether continuous exposure to shear stress is needed in induced expression of LOX-1, BAECs that had been exposed to shear stress for the indicated time periods were switched to a static condition for the residual time periods. BAECs that were exposed to shear stress for an initial 30 minutes and then cultured in a static condition showed elevated levels of LOX-1 mRNA expression after 4 hours that were almost equal to those in BAECs exposed continuously to shear stress for 4 hours (Figure 3). These results indicate that the initial changes in fluid shear stress may be crucial in the induced expression of LOX-1.

View larger version (32K): [in this window] [in a new window]   Figure 3. Effects of transient and continuous shear stress on LOX-1 mRNA induction. BAECs grown to confluence on the culture slides were incubated at 15 dyne/cm2 of shear stress () or a static condition (—-). LOX-1 mRNA levels were determined by Northern blot analysis using a bovine LOX-1 cDNA probe. Amounts of LOX-1 mRNA were measured by densitometry and were normalized with the amounts of GAPDH mRNA. One of 2 similar experiments is shown.

Shear Stress–Induced LOX-1 Expression Does Not Require De Novo Protein Synthesis
To test whether de novo protein synthesis is necessary for the shear stress–induced LOX-1 mRNA expression, cycloheximide was added to BAECs 1 hour before the application of shear stress. The inhibition of the cellular protein synthesis by cycloheximide was accompanied by increased basal LOX-1 levels, thought to be due to "superinduction," and increased LOX-1 mRNA levels in the static cells were the same as the levels in cells subjected to shear stress of 15 dyne/cm² (Figure 4). When cycloheximide-treated cells were subjected to shear stress, levels for LOX-1 mRNA in these cells were again higher than those in cycloheximide-treated cells. Taken together, de novo protein synthesis is not necessary for shear stress–induced LOX-1 gene expression, but protein synthesis inhibition superinduced LOX-1 mRNA.

View larger version (39K): [in this window] [in a new window]   Figure 4. Effect of cycloheximide on shear stress–induced LOX-1 mRNA. After confluent BAECs were preincubated with or without 50 µg/mL of cycloheximide for 30 minutes, cells were then exposed to shear stress (15 dyne/cm2) or kept under a static condition for 4 hours. Levels for LOX-1 mRNA were evaluated by Northern blot analyses. A representative result from 2 independent experiments is shown.

Shear Stress Stimulates Transcription of LOX-1 Gene
To examine whether shear stress–induced expression of LOX-1 depends on enhanced transcription of the LOX-1 gene, actinomycin D, an inhibitor of de novo mRNA synthesis, was added to BAECs 30 minutes before the application of shear stress. Pretreatment with actinomycin D completely abolished LOX-1 mRNA induction elicited by shear stress (Figure 5). These results suggest that shear stress can stimulate transcription of the LOX-1 gene.

View larger version (29K): [in this window] [in a new window]   Figure 5. Dependence of LOX-1 gene induction on de novo RNA synthesis. After pretreatment with or without actinomycin D (2.5 or 5 µg/mL) for 30 minutes, BAECs were either subjected to 15 dyne/cm2 of shear stress or cultured in a static condition for 4 hours in the presence or absence of actinomycin D (2.5 or 5 µg/mL). Total RNA was isolated from BAECs, and Northern blot analyses were performed. One of 2 similar experiments is shown.

To obtain direct evidence that LOX-1 mRNA expression was regulated at the transcriptional level, nuclear runoff assays were performed with the use of nuclei isolated from BAECs stimulated with or without fluid shear stress. Enhanced transcription of LOX-1 was observed in nuclear extracts from shear stress–treated cells compared with those kept in a static condition (Figure 6). Transcription of the GAPDH gene, in contrast, was not significantly altered by fluid shear stress. Thus, these results demonstrate that fluid shear stress stimulates transcription of the LOX-1 gene.

View larger version (48K): [in this window] [in a new window]   Figure 6. Shear stress stimulates transcription of LOX-1 gene. BAECs were grown to confluence on the culture slides and were either exposed to 15 dyne/cm2 of shear stress or kept in a static condition for 2 hours. Nuclei were isolated from BAECs, and transcriptional activities of the LOX-1 gene were assessed by a nuclear runoff assay. Transcriptional activities for GAPDH served as controls. One of 2 independent experiments is shown.

Intracellular Ca²⁺ Regulates Shear Stress–Induced Expression of LOX-1
Fluid shear stress can rapidly elevate intracellular Ca²⁺ levels; this Ca²⁺ elevation has been implicated in shear stress–induced gene expression, such as induction of NO synthase⁷ and heparin-binding epidermal growth factor–like growth factor.¹² To determine whether shear stress–mediated increases in intracellular Ca²⁺ were crucial for shear stress–induced LOX-1 expression, effects of quin 2-AM, a chelator of intracellular Ca²⁺, were examined. Pretreatment of BAECs with quin 2-AM (10 to 20 µmol/L) for 2 hours completely inhibited shear stress–induced expression of LOX-1 mRNA (Figure 7).

View larger version (28K): [in this window] [in a new window]   Figure 7. Effects of intracellular Ca2+ chelator quin 2-AM on shear stress–induced LOX-1 mRNA expression. Confluent BAECs were either preincubated with or without the indicated concentrations of quin 2-AM for 2 hours at 37°C. After they were washed, BAECs were subjected to 15 dyne/cm2 of shear stress or kept in a static condition for 4 hours. Total RNA was isolated from BAECs and subjected to Northern blot analysis. A representative figure from 2 independent experiments is shown.

We also tested whether Ca²⁺ mobilization alone is sufficient for LOX-1 induction in BAECs. Ionomycin, a Ca²⁺ ionophore, markedly induced LOX-1 mRNA in a dose-dependent manner (Figure 8). The LOX-1 mRNA level in BAECs treated with 10 µmol/L of ionomycin for 4 hours was 5.7 times higher than that in untreated BAECs. These results indicate that shear stress–induced LOX-1 expression appears to depend on intracellular Ca²⁺ mobilization.

View larger version (41K): [in this window] [in a new window]   Figure 8. Ionomycin enhances LOX-1 mRNA levels. Confluent BAECs were exposed to the indicated concentrations of ionomycin for 4 hours at 37°C. Northern blot analyses were carried out to measure LOX-1 mRNA levels. One of 2 similar results is shown.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Vascular endothelial cells are located as an interface between the bloodstream and vessel wall cells. Endothelial functions can be dynamically modulated in response to a variety of pathophysiological stimuli, including mechanical forces. In the present study, we have explored the possibility that LOX-1, a novel endothelial receptor for Ox-LDL, is also a shear stress–inducible molecule.

Inducible expression of LOX-1 by shear stress is demonstrated at both the protein and the mRNA levels in BAECs (Figures 1 and 2). Furthermore, Northern blot analyses using actinomycin D, as well as nuclear runoff assays, have revealed that shear stress can stimulate transcription of the LOX-1 gene (Figures 5 and 6). Induction of LOX-1 by fluid shear stress was relatively transient; shear stress–induced LOX-1 mRNA levels peaked at 4 hours and had decreased by 50% after 12 hours compared with the peak level. LOX-1 protein levels peaked at 8 hours and were reduced by 30% after 12 hours. These time courses of LOX-1 expression induced by shear stress are different from those observed with tumor necrosis factor-, which induced sustained levels of LOX-1 expression (data not shown), suggesting that distinct signal transduction pathways and transcriptional regulatory mechanisms are involved.

Our studies involving the transient application of shear stress in BAECs (Figure 3) show that initial stimulation with shear stress is sufficient for induced expression of LOX-1 and that sustained application of shear stress is not necessarily required. This appears to suggest that early signal transduction events elicited by shear stress may play a crucial role in LOX-1 induction. Therefore, we have focused on early events in signal transduction pathways activated by shear stress. Previous publications have shown that shear stress can stimulate phosphatidylinositol turnover, generating inositol 1,4,5-trisphosphate and 1,2-diacylglycerol²³ in cultured vascular endothelial cells. Inositol 1,4,5-trisphosphate can promote the rapid release of Ca²⁺ from endoplasmic reticulum and, thereby, raise the cytosolic free Ca²⁺ levels. Thus, the rapid increases in intracellular Ca²⁺ levels elicited by shear stress have been proposed as one of the earliest events in shear stress–induced signal transduction pathways in endothelial cells.^{20 21 22} As we have shown in Figure 7, induction of LOX-1 mRNA by shear stress was completely inhibited by chelation of intracellular Ca²⁺ with quin 2-AM. In addition, ionomycin, which raises intracellular Ca²⁺ levels, by itself increased LOX-1 mRNA levels (Figure 8). Taken together, elevated levels of intracellular Ca²⁺ were necessary and sufficient for LOX-1 gene expression elicited by shear stress.

On the other hand, 1,2-diacylglycerol, an activator of protein kinase C (PKC), also appears to be responsible for a variety of cellular responses. In fact, shear stress–induced expression of certain genes, such as PDGF,¹⁰ heparin-binding epidermal growth factor–like growth factor,¹² and c-fos,⁴¹ were shown to be mediated by PKC activation. Although both Ca²⁺ mobilization and PKC activation have been shown to be induced by fluid shear stress, our preliminary studies have shown that GF109203X, a specific inhibitor of PKC, failed to inhibit shear stress–induced LOX-1 expression (data not shown), suggesting that PKC may not play significant roles in shear stress–induced LOX-1 expression.

Fluid shear stress appears to stimulate transcription of the LOX-1 gene. Since cycloheximide did not inhibit shear stress–induced expression of LOX-1 mRNA (Figure 4), de novo synthesis of proteins, such as transcription factors, is not required in this process. NF-B can be rapidly activated, without de novo protein synthesis, by phosphorylation of inhibitor B and the subsequent dissociation from the p50/p65 complex, which are followed by nuclear translocation of p50/p65. The NF-B p50/p65 heterodimer has been shown to bind to the shear stress responsive element (SSRE) and thereby activates the SSRE-dependent gene expression, such as PDGF-B chain, in response to shear stress.^{33 42} In addition, a previous report has also indicated that AP-1, as well as NF-B, can be activated by shear stress.^{31 33} Activation of AP-1 has been shown to be responsible for shear stress–induced transcription of the monocyte chemotactic protein-1 gene.³² Involvement of AP-1 and TPA responsive element are also implicated in transcriptional downregulation of the vascular cell adhesion molecule-1 gene.^{17 43} In transcriptional regulation of PDGF-A chain by shear stress, interactions between transcription factors Sp-1 and Egr-1 have also been demonstrated.^{34 35} In the 5' flanking region of the LOX-1 gene, both consensus NF-B–like sequence and SSRE have been identified (data not shown). Further studies are necessary to elucidate the transcriptional regulatory mechanisms involved in shear stress–induced LOX-1 gene expression.

In summary, the present study provides evidence, for the first time, that physiological levels of laminar fluid flow shear stress transcriptionally induce LOX-1 expression in BAECs by a mechanism dependent on intracellular Ca²⁺ mobilization. Endothelial expression of LOX-1, a novel receptor for Ox-LDL, may also be dynamically modulated, in vivo, in response to dynamic changes in blood flow. Although pathophysiological consequences of Ox-LDL uptake by vascular endothelium through LOX-1 remain to be fully clarified, modulated expression of this Ox-LDL receptor by fluid mechanical stimuli may play an important role in the localized formation of atherosclerotic lesions in vivo.

	Acknowledgments

 
This study was supported by Grants-in-Aid for Scientific Research (Nos. 08407026, 08670788, and 09044293), for Scientific Research on Priority Areas (09281103 and 09281104), and for Creative Basic Research (09NP0601) from the Japanese Ministry of Education, Science, Sports, and Culture and by Research Grants for Cardiovascular Diseases (A8-1) from the Ministry of Health and Welfare of Japan.

Received March 5, 1998; accepted June 16, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Gimbrone MA Jr, Cybulsky MI, Kume N, Collins T, Resnick N. Vascular endothelium: an integrator of pathophysiological stimuli in atherogenesis. Ann N Y Acad Sci. 1995;748:122–132.[Medline] [Order article via Infotrieve]

2. Asakura T, Karino T. Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ Res. 1990;66:1045–1066.[Abstract/Free Full Text]

3. Malek AM, Greene AL, Izumo S. Regulation of endothelin-1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP. Proc Natl Acad Sci U S A. 1993;90:5999–6003.[Abstract/Free Full Text]

4. Morita T, Kurihara H, Maemura K, Yoshizumi M, Yazaki Y. Disruption of cytoskeletal structures mediates shear stress-induced endothelin-1 gene expression in cultured porcine aortic endothelial cells. J Clin Invest. 1993;92:1706–1712.

5. Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol. 1993;264:H150–H156.[Abstract/Free Full Text]

6. Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996;93:10417–10422.[Abstract/Free Full Text]

7. Xiao Z, Zhang Z, Diamond SL. Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J Cell Physiol. 1997;171:205–211.[Medline] [Order article via Infotrieve]

8. Lin M-C, Almus-Jacobs F, Chen H-H, Parry GCN, Mackman N, Shyy JY-J, Chien S. Shear stress induction of the tissue factor gene. J Clin Invest. 1997;99:737–744.[Medline] [Order article via Infotrieve]

9. Ohno M, Cooke JP, Dzau VJ, Gibbons GH. Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production: modulation by potassium channel blockade. J Clin Invest. 1995;95:1363–1369.

10. Hsieh HJ, Li NQ, Frangos JA. Shear-induced platelet-derived growth factor gene expression in human endothelial cells is mediated by protein kinase C. J Cell Physiol. 1992;150:552–558.[Medline] [Order article via Infotrieve]

11. Malek AM, Gibbons GH, Dzau VJ, Izumo S. Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium. J Clin Invest. 1993;92:2013–2021.

12. Morita T, Yoshizumi M, Kurihara H, Maemura K, Nagai R, Yazaki Y. Shear stress increases heparin-binding epidermal growth factor-like growth factor mRNA levels in human vascular endothelial cells. Biochem Biophys Res Commun. 1993;197:256–262.[Medline] [Order article via Infotrieve]

13. Shyy Y-J, Hsieh H-J, Usami S, Chien S. Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium. Proc Natl Acad Sci U S A. 1994;91:4678–4682.[Abstract/Free Full Text]

14. Nagel T, Resnick N, Atkinson WJ, Dewey CF Jr, Gimbrone MA Jr. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994;94:885–891.

15. Tsuboi H, Ando J, Korenaga R, Takada Y, Kamiya A. Flow stimulates ICAM-1 expression time and shear stress dependently in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;206:988–996.[Medline] [Order article via Infotrieve]

16. Ohtsuka A, Ando J, Korenaga R, Kamiya A, Toyama-Sorimachi N, Miyasaka M. The effect of flow on the expression of vascular adhesion molecule-1 by cultured mouse endothelial cells. Biochem Biophys Res Commun. 1993;193:303–310.[Medline] [Order article via Infotrieve]

17. Ando J, Tsuboi H, Korenaga R, Takada Y, Toyama-Sorimachi N, Miyasaka M, Kamiya A. Shear stress inhibits adhesion of cultured mouse endothelial cells to lymphocytes by downregulating VCAM-1 expression. Am J Physiol. 1994;267:C679–C687.[Abstract/Free Full Text]

18. Wong AJ, Pollard TD, Herman IM. Actin filament stress fibers in vascular endothelial cells in vitro. Science. 1983;219:867–869.[Abstract/Free Full Text]

19. White GE, Gimbrone MA Jr, Fujiwara K. Factors influencing the expression of stress fibers in vascular endothelial cells in situ. J Cell Biol. 1983;97:416–424.[Abstract/Free Full Text]

20. Ando J, Ohtsuka A, Korenaga R, Kawamura T, Kamiya A. Wall shear stress rather than shear rate regulates cytoplasmic Ca⁺⁺ responses to flow in vascular endothelial cells. Biochem Biophys Res Commun. 1993;190:716–723.[Medline] [Order article via Infotrieve]

21. Geiger RV, Berk BC, Alexander RW, Nerem RM. Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis. Am J Physiol. 1992;262:C1411–C1417.[Abstract/Free Full Text]

22. Shen J, Luscinskas FW, Connolly A, Dewey CF Jr, Gimbrone MA Jr. Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am J Physiol. 1992;262:C384–C390.[Abstract/Free Full Text]

23. Nollert MU, Eskin SG, McIntire LV. Shear stress increases inositol trisphosphate levels in human endothelial cells. Biochem Biophys Res Commun. 1990;170:281–287.[Medline] [Order article via Infotrieve]

24. Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K⁺ current in vascular endothelial cells. Nature. 1988;331:168–170.[Medline] [Order article via Infotrieve]

25. Gudi SRP, Clark CB, Frangos JA. Fluid flow rapidly activates G proteins in human endothelial cells: involvement of G proteins in mechanochemical signal transduction. Circ Res. 1996;79:834–839.[Abstract/Free Full Text]

26. Tseng HT, Peterson TE, Berk BC. Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. Circ Res. 1995;77:869–878.[Abstract/Free Full Text]

27. Takahashi M, Berk BC. Mitogen-activated protein kinase (ERK1/2) activation by shear stress and adhesion in endothelial cells. J Clin Invest. 1996;98:2623–2631.[Medline] [Order article via Infotrieve]

28. Jo H, Sipos K, Go YM, Law R, Rong J, McDonald JM. Differential effect of shear stress on extracellular signal-regulated kinase and N-terminal Jun kinase in endothelial cells. J Biol Chem. 1997;272:1395–1401.[Abstract/Free Full Text]

29. Li Y-S, Shyy JY-J, Li S, Lee J, Su B, Karin M, Chien S. The Ras-JNK pathway is involved in shear-induced gene expression. Mol Cell Biol. 1996;16:5947–5954.[Abstract]

30. Osawa M, Masuda M, Harada N, Lopes RB, Fujiwara K. Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur J Cell Biol. 1997;72:229–237.[Medline] [Order article via Infotrieve]

31. Lan Q, Mercurius KO, Davies PF. Stimulation of transcription factors NFkB and AP1 in endothelial cells subjected to shear stress. Biochem Biophys Res Commun. 1994;201:950–956.[Medline] [Order article via Infotrieve]

32. Shyy JY, Lin MC, Han J, Lu Y, Petrime M, Chien S. The cis-acting phorbol ester "12-O-tetradecanoylphorbol 13-acetate"-responsive element is involved in shear stress-induced monocyte chemotactic protein 1 gene expression. Proc Natl Acad Sci U S A. 1995;92:8069–8073.[Abstract/Free Full Text]

33. Khachigian LM, Resnick N, Gimbrone MA Jr, Collins T. Nuclear factor-kB interacts functionally with the platelet-derived growth factor B-chain shear-stress response element in vascular endothelial cells exposed to fluid shear stress. J Clin Invest. 1995;96:1169–1175.

34. Khachigian LM, Anderson KR, Halnon NJ, Gimbrone MA Jr, Resnick N, Collins T. Egr-1 is activated in endothelial cells exposed to fluid shear stress and interacts with a novel shear-stress-response element in the PDGF A-chain promoter. Arterioscler Thromb Vasc Biol. 1997;10:2280–2286.

35. Khachigian LM, Collins T. Inducible expression of Egr-1–dependent genes: a paradigm of transcriptional activation in vascular endothelium. Circ Res. 1997;81:457–461.[Free Full Text]

36. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990's. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]

37. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991;88:1785–1792.

38. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386:73–77.[Medline] [Order article via Infotrieve]

38A. Kume N, Murase T, Moriwaki H, Aoyama T, Sawamura T, Masaki T, Kita T. Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res. 1998;83:322–327.[Abstract/Free Full Text]

39. Nagase M, Hirose S, Sawamura T, Masaki T, Fujita T. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun. 1997;237:496–498.[Medline] [Order article via Infotrieve]

40. Kume N, Gimbrone MA Jr. Lysophosphatidylcholine transcriptionally induces growth factor expression in cultured vascular endothelial cells. J Clin Invest. 1994;93:907–911.

41. Hsieh H-J, Li N-Q, Frangos JA. Pulsatile and steady flow induces c-fos expression in human endothelial cells. J Cell Physiol. 1993;154:143–151.[Medline] [Order article via Infotrieve]

42. Resnick N, Collins T, Atkinson W, Bonthron DT, Dewey CF Jr, Gimbrone MA Jr. Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci U S A. 1993;90:4591–4595.[Abstract/Free Full Text]

43. Korenaga R, Ando J, Kosaki K, Isshiki M, Takada Y, Kamiya A. Negative transcriptional regulation of the VCAM-1 gene by fluid shear stress in murine endothelial cells. Am J Physiol. 1997;273:C1506–C1515.[Abstract/Free Full Text]

This article has been cited by other articles:

				D. Li and J. L. Mehta Intracellular Signaling of LOX-1 in Endothelial Cell Apoptosis Circ. Res., March 13, 2009; 104(5): 566 - 568. [Full Text] [PDF]

				O. L. Francone, M. Tu, L. J. Royer, J. Zhu, K. Stevens, J. J. Oleynek, Z. Lin, L. Shelley, T. Sand, Y. Luo, et al. The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding J. Lipid Res., March 1, 2009; 50(3): 546 - 555. [Abstract] [Full Text] [PDF]

				A. Bukowska, L. Schild, G. Keilhoff, D. Hirte, M. Neumann, A. Gardemann, K. H. Neumann, F.-W. Rohl, C. Huth, A. Goette, et al. Mitochondrial Dysfunction and Redox Signaling in Atrial Tachyarrhythmia Experimental Biology and Medicine, May 1, 2008; 233(5): 558 - 574. [Abstract] [Full Text] [PDF]

				J. Cheng, J. Zhang, A. Merched, L. Zhang, P. Zhang, L. Truong, A. M. Boriek, and J. Du Mechanical Stretch Inhibits Oxidized Low Density Lipoprotein-induced Apoptosis in Vascular Smooth Muscle Cells by Up-regulating Integrin {alpha}Vbeta3 and Stablization of PINCH-1 J. Biol. Chem., November 23, 2007; 282(47): 34268 - 34275. [Abstract] [Full Text] [PDF]

				J. L. Mehta, N. Sanada, C. P. Hu, J. Chen, A. Dandapat, F. Sugawara, H. Satoh, K. Inoue, Y. Kawase, K.-i. Jishage, et al. Deletion of LOX-1 Reduces Atherogenesis in LDLR Knockout Mice Fed High Cholesterol Diet Circ. Res., June 8, 2007; 100(11): 1634 - 1642. [Abstract] [Full Text] [PDF]

				J. L. Mehta, J. Chen, P. L. Hermonat, F. Romeo, and G. Novelli Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders Cardiovasc Res, January 1, 2006; 69(1): 36 - 45. [Abstract] [Full Text] [PDF]

				J.-i. Hinagata, M. Kakutani, T. Fujii, T. Naruko, N. Inoue, Y. Fujita, J. L. Mehta, M. Ueda, and T. Sawamura Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model Cardiovasc Res, January 1, 2006; 69(1): 263 - 271. [Abstract] [Full Text] [PDF]

				K. Hayashida, N. Kume, T. Murase, M. Minami, D. Nakagawa, T. Inada, M. Tanaka, A. Ueda, G. Kominami, H. Kambara, et al. Serum Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels Are Elevated in Acute Coronary Syndrome: A Novel Marker for Early Diagnosis Circulation, August 9, 2005; 112(6): 812 - 818. [Abstract] [Full Text] [PDF]

				H. Park, F. G. Adsit, and J. C. Boyington The 1.4 A Crystal Structure of the Human Oxidized Low Density Lipoprotein Receptor Lox-1 J. Biol. Chem., April 8, 2005; 280(14): 13593 - 13599. [Abstract] [Full Text] [PDF]

				A. Md Sheikh, H. Ochi, A. Manabe, and J. Masuda Lysophosphatidylcholine posttranscriptionally inhibits interferon-{gamma}-induced IP-10, Mig and I-Tac expression in endothelial cells Cardiovasc Res, January 1, 2005; 65(1): 263 - 271. [Abstract] [Full Text] [PDF]

				O. Hofnagel, B. Luechtenborg, K. Stolle, S. Lorkowski, H. Eschert, G. Plenz, and H. Robenek Proinflammatory Cytokines Regulate LOX-1 Expression in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1789 - 1795. [Abstract] [Full Text] [PDF]

				B. M. Singh and J. L. Mehta Interactions Between the Renin-Angiotensin System and Dyslipidemia: Relevance in the Therapy of Hypertension and Coronary Heart Disease Arch Intern Med, June 9, 2003; 163(11): 1296 - 1304. [Abstract] [Full Text] [PDF]

				D. Li, L. Liu, H. Chen, T. Sawamura, and J. L. Mehta LOX-1, an Oxidized LDL Endothelial Receptor, Induces CD40/CD40L Signaling in Human Coronary Artery Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 816 - 821. [Abstract] [Full Text] [PDF]

				D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, F. Romeo, and J. L. Mehta Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction J. Am. Coll. Cardiol., March 19, 2003; 41(6): 1048 - 1055. [Abstract] [Full Text] [PDF]

				L. Cominacini, A. Fratta Pasini, U. Garbin, A. Pastorino, A. Rigoni, C. Nava, A. Davoli, V. Lo Cascio, and T. Sawamura The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells J. Am. Coll. Cardiol., February 5, 2003; 41(3): 499 - 507. [Abstract] [Full Text] [PDF]

				D. Li, L. Liu, H. Chen, T. Sawamura, S. Ranganathan, and J. L. Mehta LOX-1 Mediates Oxidized Low-Density Lipoprotein-Induced Expression of Matrix Metalloproteinases in Human Coronary Artery Endothelial Cells Circulation, February 4, 2003; 107(4): 612 - 617. [Abstract] [Full Text] [PDF]

				C. R. Kiefer, J. B. McKenney, J. F. Trainor, and L. M. Snyder Maturation-Dependent Acquired Coronary Structural Alterations and Atherogenesis in the Dahl Sodium-Sensitive Hypertensive Rat Circulation, November 5, 2002; 106(19): 2486 - 2490. [Abstract] [Full Text] [PDF]

				D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, T. Antakli, and J. L. Mehta LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1795 - H1801. [Abstract] [Full Text] [PDF]

				D. Y. Li, H. J. Chen, E. D. Staples, K. Ozaki, B. Annex, B. K. Singh, R. Vermani, and J. L. Mehtat Oxidized Low-Density Lipoprotein Receptor LOX-1 and Apoptosis in Human Atherosclerotic Lesions Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2002; 7(3): 147 - 153. [Abstract] [PDF]

				D. Li, H. Chen, F. Romeo, T. Sawamura, T. Saldeen, and J. L. Mehta Statins Modulate Oxidized Low-Density Lipoprotein-Mediated Adhesion Molecule Expression in Human Coronary Artery Endothelial Cells: Role of LOX-1 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 601 - 605. [Abstract] [Full Text] [PDF]

				J. L. Mehta and D. Li Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1429 - 1435. [Abstract] [Full Text] [PDF]

				A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]

				D.Y Li, H.J Chen, and J.L Mehta Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation Cardiovasc Res, October 1, 2001; 52(1): 130 - 135. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, M. Morimoto, K. Hayashida, N. Hashimoto, and T. Kita Oxidized LDL Modulates Bax/Bcl-2 Through the Lectinlike Ox-LDL Receptor-1 in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 955 - 960. [Abstract] [Full Text] [PDF]

				T. Shimaoka, N. Kume, M. Minami, K. Hayashida, T. Sawamura, T. Kita, and S. Yonehara LOX-1 Supports Adhesion of Gram-Positive and Gram-Negative Bacteria J. Immunol., April 15, 2001; 166(8): 5108 - 5114. [Abstract] [Full Text] [PDF]

				J. L Mehta and Dayuan Li Facilitative interaction between angiotensin II and oxidised LDL in cultured human coronary artery endothelial cells Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S70 - S76. [Abstract] [PDF]

				V. Terpstra, E. S. van Amersfoort, A. G. van Velzen, J. Kuiper, and T. J. C. van Berkel Hepatic and Extrahepatic Scavenger Receptors : Function in Relation to Disease Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1860 - 1872. [Full Text] [PDF]

				L. Cominacini, A. F. Pasini, U. Garbin, A. Davoli, M. L. Tosetti, M. Campagnola, A. Rigoni, A. M. Pastorino, V. Lo Cascio, and T. Sawamura Oxidized Low Density Lipoprotein (ox-LDL) Binding to ox-LDL Receptor-1 in Endothelial Cells Induces the Activation of NF-kappa B through an Increased Production of Intracellular Reactive Oxygen Species J. Biol. Chem., April 21, 2000; 275(17): 12633 - 12638. [Abstract] [Full Text] [PDF]

				M. Chen, M. Kakutani, M. Minami, H. Kataoka, N. Kume, S. Narumiya, T. Kita, T. Masaki, and T. Sawamura Increased Expression of Lectinlike Oxidized Low Density Lipoprotein Receptor-1 in Initial Atherosclerotic Lesions of Watanabe Heritable Hyperlipidemic Rabbits Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 1107 - 1115. [Abstract] [Full Text] [PDF]

				T. Murase, N. Kume, H. Kataoka, M. Minami, T. Sawamura, T. Masaki, and T. Kita Identification of Soluble Forms of Lectin-Like Oxidized LDL Receptor-1 Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 715 - 720. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, T. Murase, T. Sawamura, T. Masaki, N. Hashimoto, and T. Kita Biosynthesis and Post-translational Processing of Lectin-like Oxidized Low Density Lipoprotein Receptor-1 (LOX-1). N-LINKED GLYCOSYLATION AFFECTS CELL-SURFACE EXPRESSION AND LIGAND BINDING J. Biol. Chem., February 25, 2000; 275(9): 6573 - 6579. [Abstract] [Full Text] [PDF]

				M. Okuda, M. Takahashi, J. Suero, C. E. Murry, O. Traub, H. Kawakatsu, and B. C. Berk Shear Stress Stimulation of p130cas Tyrosine Phosphorylation Requires Calcium-dependent c-Src Activation J. Biol. Chem., September 17, 1999; 274(38): 26803 - 26809. [Abstract] [Full Text] [PDF]

				A. M Dart and J. P.F Chin-Dusting Lipids and the endothelium Cardiovasc Res, August 1, 1999; 43(2): 308 - 322. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, H. Moriwaki, T. Murase, T. Sawamura, T. Masaki, N. Hashimoto, and T. Kita Expression of Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 in Human Atherosclerotic Lesions Circulation, June 22, 1999; 99(24): 3110 - 3117. [Abstract] [Full Text] [PDF]

				D. Y. Li, Y. C. Zhang, M. I. Philips, T. Sawamura, and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized Low-Density Lipoprotein (LOX-1) in Cultured Human Coronary Artery Endothelial Cells by Angiotensin II Type 1 Receptor Activation Circ. Res., May 14, 1999; 84(9): 1043 - 1049. [Abstract] [Full Text] [PDF]

				T. Kita LOX-1, a Possible Clue to the Missing Link Between Hypertension and Atherogenesis Circ. Res., May 14, 1999; 84(9): 1113 - 1115. [Full Text] [PDF]

				L. Cominacini, A. Rigoni, A. F. Pasini, U. Garbin, A. Davoli, M. Campagnola, A. M. Pastorino, V. Lo Cascio, and T. Sawamura The Binding of Oxidized Low Density Lipoprotein (ox-LDL) to ox-LDL Receptor-1 Reduces the Intracellular Concentration of Nitric Oxide in Endothelial Cells through an Increased Production of Superoxide J. Biol. Chem., April 20, 2001; 276(17): 13750 - 13755. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murase, T. Articles by Kita, T. Search for Related Content PubMed PubMed Citation Articles by Murase, T. Articles by Kita, T.