© 1996 American Heart Association, Inc.
Articles |
Shear Stress Modulates Expression of Cu/Zn Superoxide Dismutase in Human Aortic Endothelial Cells
the Department of Medicine (N.I., S.R., T.F., D.G.H.), Emory University School of Medicine; Veterans Administration Hospital (D.G.H.); and the Biomechanics Laboratory (R.M.N.), School of Mechanical Engineering, Georgia Institute of Technology, Atlanta.
Correspondence to David G. Harrison, Professor of Medicine, Cardiology Division, Emory University School of Medicine, Atlanta, GA 30322. E-mail dharr02@emory.edu.
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Abstract |
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A major determinant of the level of cellular superoxide anion (O2-
) is the dismutation of O2- to hydrogen peroxide by the enzyme superoxide dismutase (SOD). Three forms of SOD exist, but in endothelial cells, the major form outside of the mitochondria is the cytosolic copper/zinc-containing superoxide dismutase (Cu/Zn SOD). Since fluid shear stress is an important determinant of the function and structure of endothelial cells in vivo, we examined the effect of laminar shear stress on the expression of Cu/Zn SOD in cultured human aortic endothelial cells. Laminar shear stress of 0.6 to 15 dyne/cm2 increased Cu/Zn SOD mRNA in a time- and dose-dependent manner in human aortic endothelial cells. Shear stress also increased both Cu/Zn SOD protein content and the enzyme activity. Nuclear run-on assays showed that nuclei from human aortic endothelial cells exposed to laminar shear stress had a 1.6-fold greater transcriptional activity of the Cu/Zn SOD gene compared with cells not exposed to shear, indicating that an increase in Cu/Zn SOD mRNA induced by laminar shear stress is at least in part mediated by increased transcription. In contrast, shear stress had no effect on Cu/Zn SOD mRNA levels in human aortic smooth muscle cells. These findings show that physiological levels of shear stress increase expression of Cu/Zn SOD in the endothelium. This adaptation to shear stress might augment the effect of locally produced NO and thereby promote the antiatherogenic and anti-inflammatory properties of the endothelial cell.
Key Words: superoxide • shear stress • superoxide dismutase • hemodynamics • endothelium
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Introduction |
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Shear stress modulates endothelial cell function both acutely and over the long term by immediate and late signaling events (for review see Reference 1), by modulating endothelial cell morphology,2 and by altering gene expression.3 4 5 6 7 8 9 10 11 In vivo, levels of high shear are associated with diminished amounts of atherosclerosis, whereas regions chronically exposed to low shear demonstrate increased susceptibility to atherosclero-sis.12 13 14 15 We and others have found that chronic shear and high-flow states, such as those associated with chronic exercise training, enhance expression of the endothelial cell NO synthase and, ultimately, the capacity of the endothelium to produce NO
.11 16 17 Similarly, high-flow states are associated with enhanced endothelium-dependent vascular relaxations.18 19 The biological effect of NO is limited by the short half-life of the molecule.20 21 In vivo, particularly in the presence of disease states, a physiologically relevant factor that seems to modulate the half-life of NO is the level of production of O2-.22 23 24 25
A major determinant of the level of cellular O2- is dismutation of the radical by the enzyme SOD (EC 1.15.1.1), which enzymatically accelerates the conversion of O2- to H2O2 and molecular oxygen (for reviews, see References 26 and 27). There are three isoforms of SOD, including a cytosolic copper/zinc-containing enzyme (Cu/Zn SOD), a mitochondrial manganese enzyme (Mn SOD), and an extracellular SOD. The cytosolic Cu/Zn SOD is found widely distributed in the cell cytosol and nucleus and in most cells and is the primary nonmitochondrial enzyme regulating cellular O2- levels.28 29 In previous studies, we and others have found that release of biologically active NO is critically dependent on the endogenous endothelial cell Cu/Zn SOD.30 31 In view of these previous findings and the marked effect of shear stress on modulation of endothelium-dependent vascular relaxation,18 19 we hypothesized that chronic shear stress might enhance expression of the endothelial cell Cu/Zn SOD. To address this hypothesis, we exposed human aortic endothelial cells to various levels of shear stress and used molecular approaches to determine mRNA levels, transcriptional rate, protein expression, and enzyme activity of the cytosolic Cu/Zn SOD.
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Materials and Methods |
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Cell Culture
Human aortic endothelial and vascular smooth muscle cells were purchased from Clonetics Corp and cultured in endothelial cell growth medium purchased from Clonetics. This medium was supplemented with 7% FBS while the cells were growing and 2% FBS while the cells were exposed to shear. The control (nonsheared) cells were exposed to 2% FBS for a similar period of time.
Flow System
The flow system used in these studies has been described previously.11 17 Briefly, cells were grown to confluence and placed in a parallel-plate chamber for exposure to flow. The chamber's length was 11 cm; width, 6 cm; and height, 0.025 cm. The flow chamber was part of a closed-loop preparation in which tissue culture media passed from an upper reservoir through the flow chamber to a lower reservoir and was then recirculated, using a pump, back to the upper reservoir. Fluid temperature and pH were maintained at 37°C and 7.4, respectively. The height between the two reservoirs determined the steady flow rate.
The mean shear stress (
w) to which the cells were exposed was calculated using the following formula:
 | (E1) |
Northern Analysis
Northern analysis was performed as previously described.11 17 32 Total RNA was isolated by phenol extraction and was size-fractionated on a 1% agarose/3% formaldehyde gel and transferred to a nitrocellulose membrane. Hybridizations were performed overnight at 42°C using a [32P]dCTP-labeled full-length Cu/Zn SOD cDNA (American Type Culture Collection). The membranes were then washed with 2x SSC and 1% SDS for 15 minutes at 55°C.
Autoradiographs were quantified by densitometric scanning. Ethidium bromide staining of 18S ribosomal RNA was used as the internal standard to normalize the signal.
Western Analysis
Western analysis was performed with a sheep antibody against human Cu/Zn SOD (Biodesign International) and a rabbit anti-sheep secondary antibody conjugated to horseradish peroxidase. Signals were detected using the ECL detection system (Amersham Corp) on a standard x-ray system.
Determination of Cu/Zn SOD Enzyme Activity
The enzyme activity of SOD in the cell homogenates was assayed by monitoring inhibition of the rate of xanthine oxidase–mediated reduction of cytochrome c, as previously described.33 Human aortic endothelial cells previously exposed to either static conditions or laminar shear stress were homogenized with a Dounce homogenizer in a 50 mmol/L potassium phosphate buffer containing 0.5 mmol/L phenylmethylsulfonyl fluoride, 10 µg/mL leupeptin, and 10 µg/mL antipain. SOD activity was determined spectrophotometrically by the ability of the homogenate (50 µg total protein) to inhibit reduction of ferricytochrome c by O2- generated by the addition of xanthine and xanthine oxidase. For each experiment, a parallel determination was performed in the presence of 1 mmol/L KCN. The Cu/Zn SOD activity was calculated as the activity inhibited by KCN. Calibrations were performed using known amounts of purified bovine SOD.
Estimates of Transcription Rate
Nuclear run-on assays were performed using a method modified from that described by Greenberg.34 Briefly, endothelial cells were harvested with trypsin and centrifuged at 500g for 10 minutes. The cell pellets were suspended in buffer A containing (mmol/L) Tris-HCl 10 (pH 7.4), KCl 150, and magnesium acetate 8. After centrifugation, the cells were lysed in buffer A containing 0.5% NP-40. The cell lysates were then loaded onto buffer B containing (mmol/L) Tris-HCl 100, MgCl2 5, and sucrose 600, and the nuclei were isolated by centrifugation at 500g for 10 minutes. The nuclei were suspended in buffer C containing 40% glycerol, 50 mmol/L Tris-HCl, 5 mmol/L MgCl2, and 0.1 mmol/L EDTA and stored at -80°C until further analysis.
To perform in vitro transcription, 5x107 nuclei were suspended in a reaction buffer containing 5 mmol/L Tris-HCl (pH 8.0), 2.5 mmol/L MgCl2, 150 mmol/L KCl, 2 mmol/L each of ATP, GTP, and CTP, and 100 µCi of [
-32P]UTP for 30 minutes at 30°C. Identical numbers of nuclei from sheared and nonsheared cells were used for preparation of nascent transcripts. The reaction was stopped by the addition of RNase-free DNase by incubating for 5 minutes at 30°C. The nuclei were then lysed by the addition of buffer D containing 10 mmol/L Tris-HCl, 1% SDS, and 5 mmol/L EDTA, and the reaction mixtures were treated with 200 µg/mL of proteinase K. RNA was extracted using TRI Reagent (Molecular Research Center Inc). Equal amounts of cDNA (5 µg) for the full-length Cu/Zn SOD cDNA, human ß-actin cDNA, and a 579-bp fragment of pCAT basic vector (Promega Co) digested by Ear I and EcoRI were immobilized onto a Zeta-Probe GT membrane (Bio-Rad Laboratories) by a slot-blot apparatus (Bio-Rad Laboratories). Membranes were prehybridized for 3 hours at 65°C in a buffer containing 10 mmol/L Tris-HCl, 0.2% SDS, 10 mmol/L EDTA, 2x Denhardt's solution, 0.3 mol/L NaCl, and 0.25 mg/mL yeast tRNA. The radiolabeled transcripts (total activity, 
5x106 cpm) were added to the membrane and hybridized for 48 to 72 hours at 65°C. Care was taken to ensure that identical counts for sheared and unsheared mRNA were hybridized with the membranes. The membranes were washed twice with 2x SSC and 1% SDS for 15 minutes at 55°C and, subsequently, once with 0.2x SSC and 0.1% SDS for 30 minutes at 55°C. The membranes were exposed to a phosphor imager for quantification of transcription activity.
Materials
Radiochemicals were purchased from DuPont Corp. All other reagents were purchased from Sigma Chemical Co, except where specified.
Statistical Analysis
The data in the study are expressed as mean±SEM. Comparisons of data between control and shear were made by paired t tests and, where appropriate, by ANOVA with Fisher's least significant difference post hoc test. Values of P<.05 were considered significant.
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Results |
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Morphological Response of Human Aortic Endothelial Cells to Laminar Shear Stress
As shown in Fig 1
, human aortic endothelial cells subjected to laminar shear stress at 15 dyne/cm2 for 12 hours were elongated and aligned in the direction of flow, whereas shear did not alter the morphology of human aortic smooth muscle cells. Thus, the morphology of human aortic endothelial cells responds to shear stress in a fashion similar to that of other endothelial cells.2
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Effect of Laminar Shear Stress on Cu/Zn SOD mRNA in Human Aortic Endothelial Cells
As previously described,35 two transcripts of Cu/Zn SOD of 0.7 and 0.9 kb were detected. The 0.7-kb transcript was 4-fold more abundant than the 0.9-kb transcript in human aortic endothelial cells. Application of steady fluid shear stress at 15 dyne/cm2 resulted in a time-dependent increase in the level of both Cu/Zn SOD transcripts (Fig 2A). Levels of Cu/Zn SOD transcripts were increased as early as 2 hours after exposure to 15-dyne/cm2 laminar shear stress (Fig 2B). Maximal induction was observed at 24 hours by 2.8-fold, assessed by densitometry in four different experiments.
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Fig 2C
shows the effect of increasing levels of shear on Cu/Zn SOD mRNA in human aortic endothelial cells. Human aortic endothelial cells were exposed to varying levels of laminar shear stress from 0.6 to 15.0 dyne/cm2 for 24 hours. Increasing levels of shear stress increased Cu/Zn SOD mRNA in a dose-dependent manner (Fig 2D). Levels of mRNA were significantly increased by 3 and 15 dyne/cm2 of shear compared with 0 dyne/cm2 (P<.05). In addition, mRNA levels were increased by 15 dyne/cm2 compared with 0.6 dyne/cm2 (P<.05). In contrast, shear stress had no effect on Cu/Zn SOD mRNA levels in human vascular smooth muscle cells (Fig 2E).
Effect of Shear Stress on Cu/Zn SOD mRNA Transcriptional Rates
To determine whether the response of Cu/Zn SOD mRNA by laminar shear stress involved a change in mRNA transcription, nuclear run-on experiments were performed. Run-on transcription assays showed that the transcriptional rate of Cu/Zn SOD was increased by 1.6-fold after 5 hours of shear stress at 15 dyne/cm2. In contrast, the transcriptional rate of ß-actin was only modestly (15% and 30% in two experiments) affected by laminar shear stress (Fig 3).
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Effect of Laminar Shear Stress on Expression of Cu/Zn SOD Protein and Enzyme Activity
Protein expression of Cu/Zn SOD by laminar shear stress was assessed by Western blotting. Exposure of human aortic endothelial cells to 15 dyne/cm2 of laminar shear stress for 24 and 48 hours potentiated Cu/Zn SOD protein expression 1.3- and 2.5-fold, respectively, as assessed by densitometry (Fig 4A). Similarly, exposure of endothelial cells to 15 dyne/cm2 of shear stress for 24 hours increased the enzyme activity of Cu/Zn SOD from 1.2 to 2.2 U/mg protein (Fig 4B).
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Discussion |
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The present study demonstrates that laminar shear stress increases levels of Cu/Zn SOD mRNA, protein, and enzyme activity in human aortic endothelial cells. In the vessel, this effect of shear is likely specific for the endothelium, because shear stress did not alter the expression of Cu/Zn SOD in human vascular smooth muscle cells. Nuclear run-on assays showed that this increase in Cu/Zn SOD mRNA is at least in part due to transcriptional activation of the gene.
Several mechanisms are likely involved in the regulation of gene expression in response to shear stress. The nucleotide sequence GAGACC has been shown to be important in modulation of the promoter activity of several genes, including the platelet-derived growth factor B chain and intercellular adhesion molecule-1.5 36 It has been suggested that this core sequence interacts with NF-
B and that acute exposure of endothelial cells to shear stress causes translocation of NF-B to the nucleus.37 Of interest, the 5' flanking promoter region of the Cu/Zn SOD gene contains three copies of the sequence GAGACC at -842 bp, -2231 bp, and -3959 bp and two copies of the AP-1 binding site at -3509 bp and -3180 bp from the transcriptional start site.38 Whether or not these sequences are important in the upregulation of Cu/Zn SOD expression in response to shear remains to be determined. Of note, smooth muscle cells also contain NF-B and were not responsive to shear. This suggests that either other transcription factors are involved or that the signals proximal to activation of the NF-B are different between endothelial and vascular smooth muscle cells. Besides the GAGACC sequence, other factors have been reported to be important in shear-related changes in gene expression. Ohno et al4 have shown that transcription of transforming growth factor-ß gene by shear stress is regulated by K+ channel opening. We have also found that shear stress–induced ecNOS gene expression is regulated by K+ channel activity but not by a protein kinase C–dependent pathway.17 Monocyte chemotactic factor-1 expression is transcriptionally regulated through an AP-1 binding domain by shear stress.39
Shear stress of 15 dynes for 5 hours increased the transcription rate, as assessed by nuclear run-on, by only 1.6-fold. In preliminary studies, we found that shorter and longer exposures to shear had similar effects on the transcription rate. This finding is in contrast to levels of Cu/Zn SOD mRNA, which were increased 2- to 3-fold by shear. Although it is difficult to compare these semiquantitative data, these findings raise the possibility that shear stress might have an additional effect on Cu/Zn SOD mRNA stability. We attempted to examine this hypothesis using actinomycin D to inhibit the transcription of cells for varying periods of time after exposure to shear. Interestingly, we found that 3- to 6-hour exposures to actinomycin D caused a paradoxical increase in Cu/Zn SOD mRNA. A similar paradoxical increase in message levels after exposure to actinomycin D has been observed in the case of ornithine decarboxylase in quiescent thymocytes40 and in the case of malic enzyme regulation by thyroid-stimulating hormone.41 The explanation for this remains unclear but likely relates to the inhibition of mRNA-destabilizing proteins. Whatever the cause, this paradoxical response made examination of the stability of Cu/Zn SOD mRNA in response to shear stress difficult.
Exposure of blood vessels to higher levels of flow enhances endothelium-dependent relaxations and release of "endothelium-derived relaxing factor–like" activity, as detected by bioassay.18 19 Shear stress also increases ecNOS mRNA and protein expression (both 3-fold for shears of 15 dyne/cm2 compared with static conditions)11 and increases the endothelial cells' capacity to release NO (2-fold at 15 dyne/cm2 for 24 hours compared with static conditions),17 suggesting that the increased endothelium-derived relaxing factor–like activity in vessels exposed to high shear stress is in part caused by increased expression of ecNOS. It is known that SOD rapidly scavenges superoxide anion and prolongs the biological half-life of NO.20 21 Furthermore, it has been suggested that the endothelium may release the nitroxyl anion (NO2-) as a product of NO synthase and that SOD might increase the biological activity of nitroxyl by converting it to NO.42 Regardless of the precise mechanism, the results of the present study suggest that the augmented endothelium-dependent relaxations in the vessels exposed to high shear stress may be mediated not only by increases in ecNOS expression but also that increased expression of Cu/Zn SOD might synergistically potentiate the vasorelaxant capacity of endothelium-derived NO. Although the measured increase in SOD activity was modest, it is important to note that even a small increase in SOD activity will markedly decrease the half-life of superoxide anion.26
The distribution of hemodynamic forces is thought to have a substantial influence on the development of atherosclerosis. Pathological observations indicate that regions of low shear stress are more prone to develop atherosclerosis than regions exposed to high shear stress.13 In experimental animals, plaque formation is greater in regions with low shear stresses, whereas elevated shear stresses tend to protect against plaque formation and intimal thickening.43 The present study may in part explain these observations. It is evident now that the reaction of NO and O2- leads to the formation of peroxynitrite anion (ONOO-), which is protonated to form peroxynitrous acid.44 45 The latter can yield the hydroxyl radical and nitrogen dioxide. Peroxynitrite has been shown to produce endothelial cell injury and to oxidize sulfhydryl groups.44 Both O2- and the hydroxyl radical may contribute to oxidation of low-density lipoproteins.46 47 Recently, it has become evident that reactive oxygen species contribute to cell activation and intracellular signal transduction via redox-sensitive genes, such as vascular cell adhesion molecule-1, tissue factor, monocyte chemotactic protein-1, and others.48 49 50 51 Preservation of the half-life of NO may also have other antiatherogenic properties, such as inhibition of platelet52 and neutrophil53 adhesion and inhibition of vascular smooth muscle growth.54 Taken together, these lines of evidence suggest that induction of Cu/Zn SOD by shear might have antiatherogenic properties by reducing O2- levels and reducing the subsequent formation of peroxynitrite.
In summary, laminar shear stress upregulates Cu/Zn SOD mRNA and protein expression and increases SOD activity in human aortic endothelial cells. This response is mediated in part by transcriptional activation of the Cu/Zn SOD gene. Given the importance of oxidant stress on vascular homeostasis and the effect of Cu/Zn SOD on levels of O2-, these findings may provide new insights into how hemodynamic factors affect a variety of vascular diseases.
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Selected Abbreviations and Acronyms |
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Received January 25, 1996; accepted April 5, 1996.
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C. Yan, A. Huang, G. Kaley, and D. Sun Chronic high blood flow potentiates shear stress-induced release of NO in arteries of aged rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3105 - H3110. [Abstract] [Full Text] [PDF]
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T. M. Paravicini and R. M. Touyz Redox signaling in hypertension Cardiovasc Res, July 15, 2006; 71(2): 247 - 258. [Abstract] [Full Text] [PDF]
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S. Lehoux Redox signalling in vascular responses to shear and stretch Cardiovasc Res, July 15, 2006; 71(2): 269 - 279. [Abstract] [Full Text] [PDF]
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H. Cai A new mechanism for flow-mediated vasoprotection? Focus on "Lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species" Am J Physiol Cell Physiol, January 1, 2006; 290(1): C35 - C36. [Full Text] [PDF]
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S. C. Newcomer, U. A. Leuenberger, C. S. Hogeman, and D. N. Proctor Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H308 - H315. [Abstract] [Full Text] [PDF]
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J. Hwang, D. J. Kleinhenz, B. Lassegue, K. K. Griendling, S. Dikalov, and C. M. Hart Peroxisome proliferator-activated receptor-{gamma} ligands regulate endothelial membrane superoxide production Am J Physiol Cell Physiol, April 1, 2005; 288(4): C899 - C905. [Abstract] [Full Text] [PDF]
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N. Lauer, T. Suvorava, U. Ruther, R. Jacob, W. Meyer, D. G. Harrison, and G. Kojda Critical involvement of hydrogen peroxide in exercise-induced up-regulation of endothelial NO synthase Cardiovasc Res, January 1, 2005; 65(1): 254 - 262. [Abstract] [Full Text] [PDF]
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X. Pi, C. Yan, and B. C. Berk Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis Circ. Res., February 20, 2004; 94(3): 362 - 369. [Abstract] [Full Text] [PDF]
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P. A.C. 't Hoen, C. A.C. Van der Lans, M. Van Eck, M. K. Bijsterbosch, T. J.C. Van Berkel, and J. Twisk Aorta of ApoE-Deficient Mice Responds to Atherogenic Stimuli by a Prelesional Increase and Subsequent Decrease in the Expression of Antioxidant Enzymes Circ. Res., August 8, 2003; 93(3): 262 - 269. [Abstract] [Full Text] [PDF]
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J. Niebauer, A. J. Maxwell, P. S. Lin, D. Wang, P. S. Tsao, and J. P. Cooke NOS inhibition accelerates atherogenesis: reversal by exercise Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H535 - H540. [Abstract] [Full Text] [PDF]
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S. Dimmeler and A. M. Zeiher Exercise and Cardiovascular Health: Get Active to "AKTivate" Your Endothelial Nitric Oxide Synthase Circulation, July 1, 2003; 107(25): 3118 - 3120. [Full Text] [PDF]
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J. W. E. Rush, J. R. Turk, and M. H. Laughlin Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1378 - H1387. [Abstract] [Full Text] [PDF]
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M. E. Davis, H. Cai, L. McCann, T. Fukai, and D. G. Harrison Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1449 - H1453. [Abstract] [Full Text] [PDF]
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D. G. Peters, X.-C. Zhang, P. V. Benos, E. Heidrich-O'Hare, and R. E. Ferrell Genomic analysis of immediate/early response to shear stress in human coronary artery endothelial cells Physiol Genomics, December 26, 2002; 12(1): 25 - 33. [Abstract] [Full Text] [PDF]
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M. D. Frame, R. J. Fox, D. Kim, A. Mohan, B. C. Berk, and C. Yan Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2377 - H2385. [Abstract] [Full Text] [PDF]
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S. Adamopoulos, J. Parissis, D. Karatzas, C. Kroupis, M. Georgiadis, G. Karavolias, J. Paraskevaidis, K. Koniavitou, A. J. S. Coats, and D. T. Kremastinos Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fasligand system in patients with chronic heart failure J. Am. Coll. Cardiol., February 20, 2002; 39(4): 653 - 663. [Abstract] [Full Text] [PDF]
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Y.-M. Go, Y. C. Boo, H. Park, M. C. Maland, R. Patel, K. A. Pritchard Jr., Y. Fujio, K. Walsh, V. Darley-Usmar, and H. Jo Protein kinase B/Akt activates c-Jun NH2-terminal kinase by increasing NO production in response to shear stress J Appl Physiol, October 1, 2001; 91(4): 1574 - 1581. [Abstract] [Full Text] [PDF]
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C. R. Woodman, W. G. Schrage, J. W. E. Rush, C. A. Ray, E. M. Price, E. M. Hasser, and M. H. Laughlin Hindlimb unweighting decreases endothelium-dependent dilation and eNOS expression in soleus not gastrocnemius J Appl Physiol, September 1, 2001; 91(3): 1091 - 1098. [Abstract] [Full Text] [PDF]
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P. V. Ennezat, S. L. Malendowicz, M. Testa, P. C. Colombo, A. Cohen-Solal, T. Evans, and T. H. LeJemtel Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes J. Am. Coll. Cardiol., July 1, 2001; 38(1): 194 - 198. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [Abstract] [Full Text] [PDF]
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A. Linke, N. Schoene, S. Gielen, J.u. Hofer, S. Erbs, G. Schuler, and R. Hambrecht Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training J. Am. Coll. Cardiol., February 1, 2001; 37(2): 392 - 397. [Abstract] [Full Text] [PDF]
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J. W. E. Rush, M. H. Laughlin, C. R. Woodman, and E. M. Price SOD-1 expression in pig coronary arterioles is increased by exercise training Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2068 - H2076. [Abstract] [Full Text] [PDF]
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S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF]
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L. C.P. Azevedo, M. d. A. Pedro, L. C. Souza, H. P. de Souza, M. Janiszewski, P. L. da Luz, and F. R.M. Laurindo Oxidative stress as a signaling mechanism of the vascular response to injury: The redox hypothesis of restenosis Cardiovasc Res, August 18, 2000; 47(3): 436 - 445. [Abstract] [Full Text] [PDF]
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R. Varin, P. Mulder, F. Tamion, V. Richard, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure : Role of Nitric Oxide, Prostanoids, Oxidant Stress, and Bradykinin Circulation, July 18, 2000; 102(3): 351 - 356. [Abstract] [Full Text] [PDF]
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G. R. Drummond, H. Cai, M. E. Davis, S. Ramasamy, and D. G. Harrison Transcriptional and Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Hydrogen Peroxide Circ. Res., February 18, 2000; 86(3): 347 - 354. [Abstract] [Full Text] [PDF]
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C. Kunsch and R. M. Medford Oxidative Stress as a Regulator of Gene Expression in the Vasculature Circ. Res., October 15, 1999; 85(8): 753 - 766. [Abstract] [Full Text] [PDF]
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J. Niebauer, J.o. Dulak, J. R. Chan, P. S. Tsao, and J. P. Cooke Gene transfer of nitric oxide synthase: Effects on endothelial biology J. Am. Coll. Cardiol., October 1, 1999; 34(4): 1201 - 1207. [Abstract] [Full Text] [PDF]
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M. McIntyre, D. F. Bohr, and A. F. Dominiczak Endothelial Function in Hypertension : The Role of Superoxide Anion Hypertension, October 1, 1999; 34(4): 539 - 545. [Abstract] [Full Text] [PDF]
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T. Munzel and D. G. Harrison Increased Superoxide in Heart Failure : A Biochemical Baroreflex Gone Awry Circulation, July 20, 1999; 100(3): 216 - 218. [Full Text] [PDF]
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T. Fukai, M. R. Siegfried, M. Ushio-Fukai, K. K. Griendling, and D. G. Harrison Modulation of Extracellular Superoxide Dismutase Expression by Angiotensin II and Hypertension Circ. Res., July 9, 1999; 85(1): 23 - 28. [Abstract] [Full Text] [PDF]
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B. S. Wung, J. J. Cheng, Y. J. Chao, H. J. Hsieh, and D. L. Wang Modulation of Ras/Raf/Extracellular Signal–Regulated Kinase Pathway by Reactive Oxygen Species Is Involved in Cyclic Strain–Induced Early Growth Response-1 Gene Expression in Endothelial Cells Circ. Res., April 16, 1999; 84(7): 804 - 812. [Abstract] [Full Text] [PDF]
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L.-H. Yeh, Y. J. Park, R. J. Hansalia, I. S. Ahmed, S. S. Deshpande, P. J. Goldschmidt-Clermont, K. Irani, and B. R. Alevriadou Shear-induced tyrosine phosphorylation in endothelial cells requires Rac1-dependent production of ROS Am J Physiol Cell Physiol, April 1, 1999; 276(4): C838 - C847. [Abstract] [Full Text] [PDF]
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S. Dimmeler, C. Hermann, J. Galle, and A. M. Zeiher Upregulation of Superoxide Dismutase and Nitric Oxide Synthase Mediates the Apoptosis-Suppressive Effects of Shear Stress on Endothelial Cells Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 656 - 664. [Abstract] [Full Text] [PDF]
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C. R. Woodman, J. M. Muller, J. W. E. Rush, M. H. Laughlin, and E. M. Price Flow regulation of ecNOS and Cu/Zn SOD mRNA expression in porcine coronary arterioles Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1058 - H1063. [Abstract] [Full Text] [PDF]
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H. Drexler Endothelium as a Therapeutic Target in Heart Failure Circulation, December 15, 1998; 98(24): 2652 - 2655. [Full Text] [PDF]
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R. Hambrecht, E. Fiehn, C. Weigl, S. Gielen, C. Hamann, R. Kaiser, J. Yu, V. Adams, J. Niebauer, and G. Schuler Regular Physical Exercise Corrects Endothelial Dysfunction and Improves Exercise Capacity in Patients With Chronic Heart Failure Circulation, December 15, 1998; 98(24): 2709 - 2715. [Abstract] [Full Text] [PDF]
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S. Dimmeler, B. Assmus, C. Hermann, J. Haendeler, and A. M. Zeiher Fluid Shear Stress Stimulates Phosphorylation of Akt in Human Endothelial Cells : Involvement in Suppression of Apoptosis Circ. Res., August 10, 1998; 83(3): 334 - 341. [Abstract] [Full Text] [PDF]
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N. Inoue, S. Kawashima, K.-I. Hirata, Y. Rikitake, S. Takeshita, W. Yamochi, H. Akita, and M. Yokoyama Stretch force on vascular smooth muscle cells enhances oxidation of LDL via superoxide production Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H1928 - H1932. [Abstract] [Full Text] [PDF]
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G. W. De Keulenaer, D. C. Chappell, N. Ishizaka, R. M. Nerem, R. W. Alexander, and K. K. Griendling Oscillatory and Steady Laminar Shear Stress Differentially Affect Human Endothelial Redox State : Role of a Superoxide-Producing NADH Oxidase Circ. Res., June 1, 1998; 82(10): 1094 - 1101. [Abstract] [Full Text] [PDF]
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K. Kosaki, J. Ando, R. Korenaga, T. Kurokawa, and A. Kamiya Fluid Shear Stress Increases the Production of Granulocyte-Macrophage Colony-Stimulating Factor by Endothelial Cells via mRNA Stabilization Circ. Res., April 20, 1998; 82(7): 794 - 802. [Abstract] [Full Text] [PDF]
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L. J. Andries, D. L. Brutsaert, and S. U. Sys Nonuniformity of Endothelial Constitutive Nitric Oxide Synthase Distribution in Cardiac Endothelium Circ. Res., February 9, 1998; 82(2): 195 - 203. [Abstract] [Full Text] [PDF]
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S. Chien, S. Li, and J. Y-J. Shyy Effects of Mechanical Forces on Signal Transduction and Gene Expression in Endothelial Cells Hypertension, January 1, 1998; 31(1): 162 - 169. [Abstract] [Full Text] [PDF]
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J.J. Chiu, B.S. Wung, J. Y.J. Shyy, H.J. Hsieh, and D.L. Wang Reactive Oxygen Species Are Involved in Shear Stress-Induced Intercellular Adhesion Molecule-1 Expression in Endothelial Cells Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3570 - 3577. [Abstract] [Full Text]
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R. Korenaga, J. Ando, K. Kosaki, M. Isshiki, Y. Takada, and A. Kamiya Negative transcriptional regulation of the VCAM-1 gene by fluid shear stress in murine endothelial cells Am J Physiol Cell Physiol, November 1, 1997; 273(5): C1506 - C1515. [Abstract] [Full Text] [PDF]
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U. Solzbach, B. Hornig, M. Jeserich, and H. Just Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients Circulation, September 2, 1997; 96(5): 1513 - 1519. [Abstract] [Full Text]
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B. S. Wung, J. J. Cheng, H. J. Hsieh, Y. J. Shyy, and D. L. Wang Cyclic Strain–Induced Monocyte Chemotactic Protein-1 Gene Expression in Endothelial Cells Involves Reactive Oxygen Species Activation of Activator Protein 1 Circ. Res., July 19, 1997; 81(1): 1 - 7. [Abstract] [Full Text]
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M. D. Frame, R. J. Fox, D. Kim, A. Mohan, B. C. Berk, and C. Yan Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2377 - H2385. [Abstract] [Full Text] [PDF]
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