Published online before print October 2, 2003, doi: 10.1161/01.ATV.0000097769.47306.12
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Brief Reviews |
Regulation of Superoxide Anion Production by NADPH Oxidase in Monocytes/Macrophages
Contributions to Atherosclerosis
From the Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Martha K. Cathcart, PhD, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail cathcam{at}ccf.org
Series Editor: Marschall S. Runge
ATVB In Focus
Extracellular Mediators in Atherosclerosis and Thombosis
Previous Brief Review in this Series:
•Brasier AR, Recinos A III, Eledrisi MS. Vascular inflammation and the renin-angiotensin system. 2002;22:1257–1266.
•Moser M. Patterson C. Thrombin and vascular development: a sticky subject. 2003;23:922–930.
•Major CD, Santulli RJ, Derian CK, Andrade-Gordon P. Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. 2003;23:931–939.
•Yin Y-J, Salah Z, Grisaru-Granovsky S, Cohen I, Even-Ram SC, Maoz M, Uziely B, Peretz T, Bar-Shavit R. Human protese-activated receptor 1 expression in malignant epithelia: a role in invasiveness. 2003;23:940–944.
•Stouffer GA, Smyth SS. Effects of thrombin on interactions between ß3-integrins and extracellular matrix in platelets and vascular cells. 2003;23:1971–1978.
 |
Abstract |
|---|
Monocyte extravasation into the vessel wall has been shown to be a critical step in the development of atherosclerosis. Upon activation, monocytes produce a burst of superoxide anion due to activation of the NADPH oxidase enzyme complex. Monocyte-derived superoxide anion contributes to oxidant stress in inflammatory sites, is required for monocyte-mediated LDL oxidation, and alters basic cell functions such as adhesion and proliferation. We hypothesize that monocyte-derived superoxide anion production contributes to atherosclerotic lesion formation. In this brief review, we summarize our current understanding of the signal transduction pathways regulating NADPH oxidase activation and related superoxide anion production in activated human monocytes. Novel pathways are identified that may serve as future targets for therapeutic intervention in this pathogenic process. The contributions of superoxide anion and NADPH oxidase to atherogenesis are discussed. Future experiments are needed to clarify the exact role of NADPH oxidase-derived superoxide anion in atherogenesis, particularly that derived from monocytes.
Key Words: monocyte • macrophage • superoxide anion • NADPH oxidase • atherosclerosis
|
Introduction |
|---|
Atherosclerosis is a chronic inflammatory disease of the vessel wall characterized by the archetypal chronic inflammatory cell infiltrate of macrophages. The protective versus pathologic role for monocytes/macrophages in disease progression has not been fully delineated, but the conversion of these cells into characteristic lipid-laden foam cells suggests that the macrophage is exposed to an overwhelming burden of lipid and cell debris that might paralyze any protective role that may have preceded. Evidence indicates that atherosclerotic lesion development is dramatically compromised if monocytes are prevented from entering the blood vessel wall and thus a pathologic contribution is indicated.1–3
When circulating in blood, monocytes are resting cells poised to respond to an activating stimulus. In response to such a stimulus, monocytes adhere to activated endothelial cells on the blood vessel wall and extravasate into the adjacent tissue. While residing in the tissue, they differentiate to monocyte-derived macrophages. One of the most immediate responses of monocytes to a variety of activating stimuli is the production of the potent oxygen free radical, superoxide anion. The enzyme complex primarily responsible for the production of this highly reactive oxygen species is the NADPH oxidase complex. Recent studies in mice rendered deficient in a central component of the oxidase have revealed that NADPH oxidase–deficient animals develop significantly less atherosclerosis, as assessed by measuring total atherosclerotic lesion area.4 Therefore, understanding the regulation of the activity of this important enzyme complex may lead to novel therapeutic interventions for preventing atherosclerosis.
Data clearly indicate that monocytes actively contribute to atherosclerotic lesion development.1–3,5 The production of superoxide anion, as outlined above, also significantly contributes to lesion development. Although many cells in the vascular wall have been shown to be able to produce superoxide anion, monocytes/macrophages are likely a significant source of NADPH oxidase–derived superoxide anion in atherosclerotic lesions. It is therefore reasonable to suggest that monocyte/macrophage-derived superoxide anion participates in the pathogenesis of atherosclerosis.
The regulation of the activity of NADPH oxidase in primary human monocyte/macrophages, the predominant inflammatory cell in atherosclerotic vessels, has been the focus of several years of research in our laboratory. This review summarizes our present understanding of the regulation of NADPH oxidase activity in monocyte/macrophages and compares and contrasts the enzyme complex components and oxidase regulation to that in neutrophils and to the related enzyme oxidase complexes expressed in other arterial cells, such as vascular smooth muscle cells. For all of our research, we have activated the monocytic NADPH oxidase using opsonized zymosan, a mimic of a yeast pathogen and a potent NADPH oxidase activator. Clearly, other activators of this complex are present in inflammatory sites, including cytokines. We have identified numerous pathways that are important regulators of NADPH oxidase activation by opsonized zymosan. Although opsonized zymosan is not the likely activator of the oxidase complex in atherosclerosis, it is likely that some of these regulatory pathways are shared. Indeed, it has recently been shown that several regulatory pathways are similar between angiotensin II stimulation of NADPH oxidase and that observed in our model system.6–8 These regulatory pathways are potential therapeutic targets for regulating superoxide anion production and controlling chronic inflammation. Additional research is needed to identify the best pathways to target in order to intervene in the pathologic contributions of this enzyme complex.
|
Monocyte NADPH Oxidase |
|---|
In resting primary human monocytes, the NADPH oxidase complex is unassembled and its components are located in the cytosol and the membrane. Upon activation, the cytosolic components translocate to the membrane and associate with the membrane components, and the newly formed enzyme complex actively catalyzes the production of superoxide anion. The membrane components include the cytochrome b558, consisting of gp91phox and p22phox. Cytosolic components include p47phox, p67phox, and Rac1 (Figure). The NADPH oxidase components in neutrophils are similar to those in monocytes/macrophages with the exception of the latter protein. Instead of Rac1, Rac2, another Rho family member of small G-proteins, is a component of the neutrophil NADPH oxidase.8 This latter, recent finding may provide a novel target for therapy that might allow discrimination between therapies that target chronic versus acute inflammatory responses.
|
Evidence indicates that the NADPH oxidase of monocytes resembles, but is regulated differently than, the well-studied NADPH oxidase enzyme complex of neutrophils.9 Some examples of these differences are that neutrophils, on stimulation, produce a more immediate respiratory burst (peaking at 2 to 10 minutes, depending on the stimulus), whereas monocytes gradually increase production of superoxide anion. They have peak production at 
1 hour that wanes over time but is still detectable after several hours.10,11 Furthermore, after stimulation of monocytes to activate NADPH oxidase, the cells can mount an additional response after sufficient recovery and restimulation. This process is not observed in neutrophils. These differences may contribute to the distinct roles of monocytes/macrophages and neutrophils in chronic versus acute inflammation.11 Additionally, agents that activate NADPH oxidase in neutrophils do not necessarily trigger the NADPH oxidase in monocytes/macrophages, indicating differential regulation likely through alternative signal transduction pathways.12 Thus, it is important to understand the unique pathways regulating NADPH oxidase activity in monocytes.
Because most of what we know about NADPH oxidase regulation and activity has been derived from cell-free components of neutrophils or from intact neutrophils, our laboratory has focused on defining the regulation of NADPH oxidase assembly and activation in monocytes/macrophages. An additional key reason for focusing on understanding this process in monocytes derives from the fact that whereas NADPH oxidase has been shown to promote atherogenesis, neutrophils are not present in the vessel wall either early or late in lesion development. Although other vascular cells express similar oxidases, monocytes/macrophages are a plausible source of superoxide anion in this disease.13
Most of our studies have been conducted on peripheral blood monocytes, isolated by adherence to serum-coated plastic and studied within 24 hours. We therefore refer to the cells prepared in this fashion as monocytes/macrophages. We have confirmed most of our observations in elutriated monocytes and monocyte-derived macrophages (monocytes cultured for 7 to 10 days) and have as yet observed no differences in the regulation of NADPH oxidase activity between these related cells.
It should also be noted that we have focused our studies on the induction of NADPH oxidase activity during the first hour after exposure to the activator; thus, altered gene expression does not contribute to our observations. In contrast, expression of NADPH oxidase components can be induced by treatment with cytokines or growth factors in smooth muscle cells and monocytes/macrophages.14–16 This likely contributes to the magnitude of superoxide production by these cells but is not a factor in our studies.
|
Calcium Influx and Release Are Required |
|---|
To begin to understand the regulation of this important enzyme complex in monocytes, we examined the role of intracellular calcium mobilization and calcium influx in monocyte-mediated superoxide anion production. Our studies indicated that both calcium influx through receptor-regulated channels and mobilization of intracellular calcium were crucial events for monocyte oxidation of lipids, a superoxide anion–dependent event.17 Because raising intracellular calcium can have profound effects on several other signal transduction pathways, particularly the calcium-dependent protein kinase C (PKC) and cytosolic phospholipase A2 (cPLA2) pathways, we next evaluated the involvement of these enzymes in regulating NADPH oxidase activity.
|
cPLA2 Activity Regulates Monocyte/Macrophage NADPH Oxidase |
|---|
Phospholipases A2 (PLA2s) are enzymes that catalyze the hydrolysis of fatty acids from the sn-2 position of a wide variety of phospholipids. PLA2s have been shown to be important for supplying unsaturated fatty acids to lipid oxidation enzymes, eg, cyclooxygenases and lipoxygenases, as well as for generating lysophospholipids that also serve as potent regulatory molecules. Several different, molecularly unrelated PLA2 enzymes have been reported in the literature.18–20 Among these, cPLA2 is rapidly activated by increased concentrations of intracellular calcium (in the micromolar range), which causes translocation from the cytosol to the membrane/particulate fraction of the cells. We found that cPLA2 expression is barely detectable in unactivated monocytes. cPLA2 expression is substantially induced by activation of monocytes with opsonized zymosan. As cPLA2 protein expression is induced, cPLA2 phosphorylation and enzymatic activity are increased in parallel (Q. Li et al, unpublished data, 2003).21
When cPLA2 activity was inhibited with pharmacologic inhibitors or cPLA2 protein expression was inhibited by treatment with specific antisense oligodeoxyribonucleotides (ODN), NADPH oxidase activity was impaired. Importantly, the addition of one of the major products of cPLA2 activity, arachidonic acid (AA), restored NAPDH oxidase activity in the cPLA2-deficient monocytes.21 This result indicated that the production of AA by cPLA2 was an essential regulator of monocyte/macrophage NADPH oxidase activity (see the scheme in the Figure).
To additionally understand the role for cPLA2 and its product AA in regulating NADPH oxidase activity, we conducted a series of experiments exploring the effect of blocking cPLA2 expression on the phosphorylation and assembly of the central NADPH oxidase components p47phox and p67phox. These studies revealed that oxidase assembly was blocked when cPLA2 expression was inhibited by treatment with antisense ODN.23 Specifically, the cytosol to membrane translocation of p47phox and p67phox was prevented in cPLA2-deficient monocytes. The addition of AA to cPLA2-deficient monocytes restored translocation of both p47phox and p67phox, thus allowing the normal, activation-induced assembly of the oxidase and superoxide anion production.23 These results strongly support the conclusion that AA, derived from cPLA2 activity, contributes to the translocation of essential NADPH oxidase components, allowing for assembly of the active enzyme complex. Our laboratory is presently investigating the mechanisms whereby AA regulates the translocation of NADPH oxidase components (summarized in the Figure).
|
Regulation of NADPH Oxidase by Component Phosphorylation: Protein Kinase C Is Essential |
|---|
Phosphorylation of p47phox and p67phox also regulates NADPH oxidase activity. p47phox and p67phox were both shown to be phosphorylated in response to activation of monocytes with opsonized zymosan. Both components also translocated to the membrane from the cytosol.23 Inhibition of phosphorylation with general serine/threonine kinase inhibitors blocked both the phosphorylation and translocation (E.A. Bey and M.K. Cathcart, unpublished data, 2003; X. Zhao and M.K. Cathcart, unpublished data, 2003). Phosphorylation of these central NADPH oxidase components was not affected by inhibition of cPLA2 expression or enzymatic activity.23 These findings suggest that phosphorylation precedes translocation and represents yet another level of control of this enzyme.
PKC comprises an enzyme family that mediates the phosphorylation of serine and threonine on proteins with particular amino acid motifs. The PKC family is comprised of several isoenzymes that can be distinguished from each other by amino acid sequence, calcium dependence, phospholipid regulation, substrate specificity, and intracellular localization. Members of this enzyme family serve as important mediators of signal transduction. The PKC family is comprised of several isoenzymes (presently 12 members). They can be divided into 3 subtypes: cPKC (classical PKC), nPKC (novel PKC), and aPKC (atypical PKC).26–28
Our early studies indicated a requirement for PKC activity in the activation of the NADPH oxidase. We showed that monocytes express several PKC isoforms, including PKC
, PKCßI, PKCßII, PKC
, PKC
, and PKC
. The expression of each of these isoforms was induced upon monocyte activation.7 PKC activity also increased and translocated from the soluble to the particulate cell fraction. The activity of the cPKC group of PKC isoenzymes is regulated by calcium, and, based on our prior studies showing the critical role for calcium, this group was therefore singled out as a likely participant for regulating NADPH oxidase. The cPKC isoenzymes consist of PKC, PKCßI, PKCßII, and PKC
. PKC inhibitors and antisense ODN specific for a conserved mRNA sequence shared among the cPKC family members blocked NADPH oxidase activity.29 The cPKC isoenzymes expressed in monocytes are PKC, PKCßI, and PKCßII. Additional studies using isoenzyme-specific antisense ODN revealed that PKC was required for superoxide anion production and the related oxidation of LDL, whereas PKCßI and PKCßII were not involved.7
|
Relationship Between PKC and cPLA2
|
|---|
cPLA2 activity is regulated not only by calcium but also by phosphorylation. Lin et al30 have shown that activation of cPLA2 is associated with increased serine phosphorylation. Activation of monocyte PKC, as well as induction of calcium release from internal stores or calcium influx, all enhance PLA2 activity.31 Likewise, inhibitors of PKC have been shown to block agonist-induced cPLA2 activity.32,33 cPLA2 also contains a consensus site for phosphorylation by mitogen-activated protein (MAP) kinase; indeed, recent studies show that MAP kinase phosphorylation activates cPLA2 in vitro.34 Using PD098059, a selective inhibitor of the immediate upstream activator of MAP kinase, the dual-specificity kinase called MEK, we have recently shown that although monocyte/macrophage MAP kinase activation is substantially blocked by this drug, cPLA2 activity remains unaffected. In contrast, PKC
was shown to be required for mediating the phosphorylation and activation of cPLA2. When monocytes were rendered deficient in PKC expression, also using specific antisense ODN, the activity of NADPH oxidase could be restored by AA.7 This finding reveals that PKC is solely required for mediating the phosphorylation and activation of cPLA2 and thereby regulates the production of superoxide anion (Q. Li et al, unpublished data, 2003) (Figure).
Although the aforementioned studies demonstrate that PKC is the cPKC enzyme that is required for NADPH oxidase activity, these studies do not rule out the involvement of other PKC isoenzymes in regulating superoxide anion production by NADPH oxidase, eg, members of the aPKC and nPKC groups. In addition to the dedicated role of PKC in regulating NADPH oxidase activity via cPLA2, we have recently discovered that another PKC isoform regulates NADPH oxidase activity.
Using a pharmacologic inhibitor and specific antisense ODN, our recent studies indicate that PKC expression and activity are also required for NADPH oxidase activity. Our results indicate that PKC is required for the phosphorylation of both p47phox and p67phox (E.A. Bey and M.K. Cathcart, unpublished data, 2003; X. Zhao and M.K. Cathcart, unpublished data, 2003). Translocation of both of these NADPH oxidase components is also regulated by PKC. It thus appears that PKC controls the phosphorylation of both p47phox and p67phox and regulates their translocation to the membrane fraction and controls the assembly of the active NADPH oxidase complex.
We are careful to interpret these data at face value. Although it is tempting to speculate that PKC directly phosphorylates p47phox and p67phox, our data do not prove that this is the case. Our studies indicate that PKC regulates phosphorylation of these components, but direct phosphorylation in vivo remains to be determined. To begin to assess this, we examined whether recombinant PKC could phosphorylate p47phox and p67phox in vitro and found that both NADPH oxidase components were directly phosphorylated (E.A. Bey and M.K. Cathcart, unpublished data, 2003; X. Zhao and M.K. Cathcart, unpublished data, 2003). We are now investigating the location of the phosphorylation sites on p47phox and p67phox obtained in vitro and are comparing them to those that are induced in intact cells on monocyte activation.
|
Superoxide Anion, NADPH Oxidase, and Atherosclerosis |
|---|
 TopAbstractIntroductionMonocyte NADPH OxidaseCalcium Influx and Release...cPLA2 Activity Regulates...Regulation of NADPH Oxidase...Relationship Between PKC{alpha}... Superoxide Anion, NADPH Oxidase,... References |
|---|
One way that superoxide anion is presumed to participate in atherogenesis is through the formation of oxidized lipids, particularly oxidized LDL. The altered bioactivity of oxidized compared with unoxidized LDL was first reported by Chisolm and colleagues.35,36 Shortly thereafter, our laboratory showed that monocytes/macrophages, the major inflammatory cell component of atherosclerotic lesions, could cause LDL oxidation.37 Thus, the hypothesis was formed that macrophage oxidation of LDL contributes to the pathogenesis of atherosclerosis.
Among the proatherogenic properties of oxidized LDL is the characteristic unregulated uptake of this modified lipoprotein by macrophages that thereby contributes to the formation of foam cells. Numerous other proatherogenic biologic activities have been attributed to oxidized LDL.38
As mentioned, our laboratory was the first to demonstrate that activated monocytes could oxidize LDL.37,39 This was found to be a unique activity of leukocytes, because they are the only lesion cells that oxidize LDL in the absence of added free metal ions.40 Macrophage-mediated LDL oxidation was shown to be entirely dependent on the production of superoxide anion by the NADPH oxidase enzyme complex.10,41
In atherosclerotic lesions, oxidized lipids are believed to be formed not only by free radical oxidation but also by a variety of enzymatic pathways, including cyclooxygenases and lipoxygenases. We found that oxidized lipid products of 15-lipoxygenase are present in human atherosclerotic lesions, and others have documented that 15-lipoxygenase is expressed in lesion macrophages.42,43 Myeloperoxidase and ceruloplasmin have also been implicated in mediating lipid and LDL oxidation in atherosclerotic lesions.40 It is important to note that superoxide anion is an important mediator of LDL oxidation both as a reactive oxygen radical and as a required substrate or cofactor in the oxidation reactions catalyzed by these enzymes, particularly myeloperoxidase, ceruloplasmin, and lipoxygenases.
Superoxide anion, in addition to mediating LDL oxidation, may contribute to the pathogenesis of atherosclerosis in a variety of other ways. Among these, the production of reactive oxygen species induces stress responses that alter cell function, including adhesion, proliferation, and motility. Superoxide anion is also a very effective scavenger of nitric oxide and can thereby regulate endothelial relaxation and in the process also generate highly reactive peroxynitrite. Thus, superoxide anion has the potential to contribute to atherosclerosis in numerous ways.
NADPH oxidase has been assessed for its contributions to the development of atherosclerosis in mice. Three studies have been performed in animals with gene knockouts of either of 2 central components of this enzyme complex (p47phox or gp91phox).4,44,45 All 3 studies indicate that NADPH oxidase has little or no effect on the development of atherosclerosis in the aortic sinus. In contrast, however, 1 study evaluated total aortic lesions rather than those localized to the aortic sinus. In this study, lesions were dramatically decreased in the p47phox-null, NADPH oxidase–deficient animals.4 The interpretation of these observations was that aortic sinus lesions may be more advanced and differences between the NADPH oxidase-deficient and control animals might be difficult to detect at this stage of lesion development. This interpretation remains to be confirmed.
In addition to the NADPH oxidases of monocytes and neutrophils, several other cell types have been reported to have lower-activity NAD(P)H oxidases. It is believed that the lower production of superoxide anion may function as a second messenger, regulating basic cell functions such as cell growth. This is in striking contrast to the high-activity NADPH oxidase of phagocytes that, in addition to serving as intracellular signaling molecules, also is produced in sufficient quantities for killing microorganisms, mediating tissue injury, and oxidizing lipoproteins. This latter feature of monocyte-derived superoxide anion is believed to contribute to the pathogenesis of atherosclerosis as outlined above; however, the relative contributions of NADPH oxidases from different cell sources remains to be determined.
In the murine studies described above, none of the genetic knockouts were cell- or tissue-specific. It is therefore not possible to determine which cell type, among those with the capacity to produce superoxide anion by this or a similar enzyme complex, was responsible for the observed protection against atherosclerosis. It is important to pursue these studies to discriminate between monocyte/macrophage NADPH oxidase and that of smooth muscle cells or endothelial cells in this disease process. It is of utmost importance to evaluate total aortic lesions in the gp91phox-null animals, because gp91phox is important for phagocyte NADPH oxidase but not for the NAD(P)H oxidase complex of smooth muscle cells. Additional confirmation with bone marrow transplants from p47phox-null mice into atherosclerosis-prone animals would also clarify the source of the disease-promoting NADPH oxidase activity observed in the studies by Barry-Lane et al.4
In summary, it is likely that superoxide anion functions at several different levels in contributing to the pathologic processes in atherosclerotic lesions. Superoxide anion likely participates in direct lipid and lipoprotein oxidation reactions, leading to foam cell formation, and also serves as a precursor for mediating myeloperoxidase and ceruloplasmin oxidation of lipids. Superoxide anion, either directly or indirectly, may alter vascular cell behavior, gene expression, and injury. Each of these roles could significantly contribute to lesion development. Additional experiments are needed to determine the importance of monocyte/macrophage-derived superoxide anion in the pathogenesis of atherosclerosis and to identify the critical regulatory pathways that could serve as targets for therapeutic intervention.
The goal in designing therapeutic agents to regulate monocyte/macrophage NADPH oxidase is to preserve the function of the enzyme complex so that it can function properly in host defense while regulating excessive and chronic superoxide anion production that seems to contribute to inflammatory injury. Identification of the molecular pathways, such as those summarized in the Figure, that regulate NADPH oxidase assembly and activity will help to ascertain the optimal pathways for controlling oxidase activation.
|
Acknowledgments |
|---|
Acknowledgments
The major contributions of the following laboratory members to the work reviewed in this study are greatly appreciated: Venkita Subbulakshmi, Claudine Horton, and Drs Amy McNally, Qing Li, Virginia Folcik, Erik Bey, and Xiaoxian Zhao.
Received May 9, 2003; accepted September 16, 2003.
|
References |
|---|
1. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394: 894–897.[CrossRef][Medline] [Order article via Infotrieve]
2. Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ, Charo IF. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest. 1999; 103: 773–778.[Medline] [Order article via Infotrieve]
3. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
4. Barry-Lane PA, Patterson C, van der Merwe M, Hu Z, Holland SM, Yeh ET, Runge MS. p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Invest. 2001; 108: 1513–1522.[CrossRef][Medline] [Order article via Infotrieve]
5. Aiello RJ, Bourassa PA, Lindsey S, Weng W, Natoli E, Rollins BJ, Milos PM. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 1999; 19: 1518–1525.
6. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res. 2002; 91: 406–413.
7. Li Q, Subbulakshmi V, Fields AP, Murray NR, Cathcart MK. Protein kinase C alpha regulates human monocyte O-2 production and low density lipoprotein lipid oxidation. J Biol Chem. 1999; 274: 3764–3771.
8. Zhao X, Carnevale KA, Cathcart MK. Human monocytes use Rac1, not Rac2, in the NADPH oxidase complex. J Biol Chem. 2003; 278: 40788–40792.
9. Leusen JH, Verhoeven AJ, Roos D. Interactions between the components of the human NADPH oxidase: intrigues in the phox family. J Lab Clin Med. 1996; 128: 461–476.[CrossRef][Medline] [Order article via Infotrieve]
10. Cathcart MK, McNally AK, Morel DW, Chisolm GM. Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein and conversion of low-density lipoprotein to a cytotoxin. J Immunol. 1989; 142: 1963–1969.[Abstract]
11. Dewald B, Payne TG, Baggiolini M. Activation of NADPH oxidase of human neutrophils: potentiation of chemotactic peptide by a diacylglycerol. Biochem Biophys Res Commun. 1984; 125: 367–373.[CrossRef][Medline] [Order article via Infotrieve]
12. Klebanoff SJ. Oxygen metabolites from phagocytes. In: Gallin JI, ed. Inflammation. New York: Raven Press; 1992.
13. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
14. Dusi S, Donini M, Lissandrini D, Mazzi P, Bianca VD, Rossi F. Mechanisms of expression of NADPH oxidase components in human cultured monocytes: role of cytokines and transcriptional regulators involved. Eur J Immunol. 2001; 31: 929–938.[CrossRef][Medline] [Order article via Infotrieve]
15. Eklund EA, Kakar R. Recruitment of CREB-binding protein by PU1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression. J Immunol. 1999; 163: 6095–6105.
16. Kalinina N, Agrotis A, Tararak E, Antropova Y, Kanellakis P, Ilyinskaya O, Quinn MT, Smirnov V, Bobik A. Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2002; 22: 2037–2043.
17. Li Q, Tallant A, Cathcart MK. Dual Ca2+ requirement for optimal lipid peroxidation of low density lipoprotein by activated human monocytes. J Clin Invest. 1993; 91: 1499–1506.
18. Kudo I, Murakami M, Hara S, Inoue K. Mammalian non-pancreatic phospholipases A2. Biochim Biophys Acta. 1993; 1170: 217–231.[Medline] [Order article via Infotrieve]
19. Kramer RM, Sharp JD. Structure, function and regulation of Ca2+-sensitive cytosolic phospholipase A2 (cPLA2). FEBS Lett. 1997; 410: 49–53.[CrossRef][Medline] [Order article via Infotrieve]
20. Leslie CC. Properties and regulation of cytosolic phospholipase A2. J Biol Chem. 1997; 272: 16709–16712.
21. Li Q, Cathcart MK. Selective inhibition of cytosolic phospholipase A2 in activated human monocytes: regulation of superoxide anion production and low density lipoprotein oxidation. J Biol Chem. 1997; 272: 2404–2411.
23. Zhao X, Bey EA, Wientjes FB, Cathcart MK. Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67(phox) and p47(phox). J Biol Chem. 2002; 277: 25385–25392.
26. Azzi A, Boscoboinik D, Hensey C. The protein kinase C family. Eur J Biochem. 1992; 208: 547–557.[Medline] [Order article via Infotrieve]
27. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992; 258: 607–614.
28. Hug H, Sarre TF. Protein kinase C isoenzymes: divergence in signal transduction? Biochem J. 1993; 291: 329–343.
29. Li Q, Cathcart MK. Protein kinase C activity is required for lipid oxidation of low density lipoprotein by activated human monocytes. J Biol Chem. 1994; 269: 17508–17515.
30. Lin LL, Lin AY, Knopf JL. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc Natl Acad Sci U S A. 1992; 89: 6147–6151.
31. Majumdar S, Rossi MW, Fujiki T, Phillips WA, Disa S, Queen CF, Johnston RB Jr, Rosen OM, Corkey BE, Korchak HM. Protein kinase C isotypes and signaling in neutrophils: differential substrate specificities of a translocatable calcium- and phospholipid-dependent beta-protein kinase C and a phospholipid-dependent protein kinase which is inhibited by long chain fatty acyl coenzyme A. J Biol Chem. 1991; 266: 9285–9294.
32. Wijkander J, Gewert K, Svensson U, Holst E, Sundler R. Multiple C-terminal serine phosphorylation accompanies both protein kinase C-dependent and -independent activation of cytosolic 85 kDa phospholipase A2 in macrophages. Biochem J. 1997; 325: 405–410.
33. Winitz S, Gupta SK, Qian NX, Heasley LE, Nemenoff RA, Johnson GL. Expression of a mutant Gi2 alpha subunit inhibits ATP and thrombin stimulation of cytoplasmic phospholipase A2-mediated arachidonic acid release independent of Ca2+ and mitogen-activated protein kinase regulation. J Biol Chem. 1994; 269: 1889–1895.
34. Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ. cPLA2 is phosphorylated and activated by MAP kinase. Cell. 1993; 72: 269–278.[CrossRef][Medline] [Order article via Infotrieve]
35. Hessler JR, Morel DW, Lewis LJ, Chisolm GM. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis. 1983; 3: 215–222.
36. Morel DW, Hessler JR, Chisolm GM. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res. 1983; 24: 1070–1076.[Abstract]
37. Cathcart MK, Morel DW, Chisolm GMd. Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukoc Biol. 1985; 38: 341–350.[Abstract]
38. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28: 1815–1826.[CrossRef][Medline] [Order article via Infotrieve]
39. Cathcart MK, Chisolm GM, McNally AK, Morel DW. Oxidative modification of low density lipoprotein (LDL) by activated human monocytes and the cell lines U937 and HL60. In Vitro Cell Dev Biol. 1988; 24: 1001–1008.[Medline] [Order article via Infotrieve]
40. Chisolm GM, 3rd, Hazen SL, Fox PL, Cathcart MK. The oxidation of lipoproteins by monocytes-macrophages: biochemical and biological mechanisms. J Biol Chem. 1999; 274: 25959–25962.
41. Bey EA, Cathcart MK. In vitro knockout of human p47phox blocks superoxide anion production and LDL oxidation by activated human monocytes. J Lipid Res. 2000; 41: 489–495.
42. Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Sigal E, Sarkioja T, Witztum JL, Steinberg D. Gene expression in macrophage-rich human atherosclerotic lesions: 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts. J Clin Invest. 1991; 87: 1146–1152.
43. Folcik VA, Nivar-Aristy RA, Krajewski LP, Cathcart MK. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J Clin Invest. 1995; 96: 504–510.
44. Kirk EA, Dinauer MC, Rosen H, Chait A, Heinecke JW, LeBoeuf RC. Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2000; 20: 1529–1535.
45. Hsich E, Segal BH, Pagano PJ, Rey FE, Paigen B, Deleonardis J, Hoyt RF, Holland SM, Finkel T. Vascular effects following homozygous disruption of p47(phox): an essential component of NADPH oxidase. Circulation. 2000; 101: 1234–1236.
This article has been cited by other articles:
 |
|
 |
|
  F. Violi, V. Sanguigni, R. Carnevale, A. Plebani, P. Rossi, A. Finocchi, C. Pignata, D. De Mattia, B. Martire, M. C. Pietrogrande, et al. Hereditary Deficiency of gp91phox Is Associated With Enhanced Arterial Dilatation: Results of a Multicenter Study Circulation, October 20, 2009; 120(16): 1616 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fortuno, J. Bidegain, P. A. Robador, J. Hermida, J. Lopez-Sagaseta, O. Beloqui, J. Diez, and G. Zalba Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C: Potential Clinical Implications in Hypertension Hypertension, October 1, 2009; 54(4): 744 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Moore and A. B. MacKenzie NADPH Oxidase NOX2 Mediates Rapid Cellular Oxidation following ATP Stimulation of Endotoxin-Primed Macrophages J. Immunol., September 1, 2009; 183(5): 3302 - 3308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Dai, M. Jayapal, H. K. Tay, R. Reghunathan, G. Lin, C. T. Too, Y. T. Lim, S. H. Chan, D. M. Kemeny, R. A. Floto, et al. Differential signal transduction, membrane trafficking, and immune effector functions mediated by Fc{gamma}RI versus Fc{gamma}RIIa Blood, July 9, 2009; 114(2): 318 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Leeper, M. M. Tedesco, Y. Kojima, G. M. Schultz, R. K. Kundu, E. A. Ashley, P. S. Tsao, R. L. Dalman, and T. Quertermous Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1329 - H1335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Liu, Y.-H. Li, G.-Y. Shi, S.-H. Tang, S.-J. Jiang, C.-W. Huang, P.-Y. Liu, J.-S. Hong, and H.-L. Wu Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice Cardiovasc Res, April 1, 2009; 82(1): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Bae, J. H. Lee, S. H. Choi, S. Kim, F. Almazan, J. L. Witztum, and Y. I. Miller Macrophages Generate Reactive Oxygen Species in Response to Minimally Oxidized Low-Density Lipoprotein: Toll-Like Receptor 4- and Spleen Tyrosine Kinase-Dependent Activation of NADPH Oxidase 2 Circ. Res., January 30, 2009; 104(2): 210 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jun, V. Savransky, A. Nanayakkara, S. Bevans, J. Li, P. L. Smith, and V. Y. Polotsky Intermittent hypoxia has organ-specific effects on oxidative stress Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1274 - R1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lemarie, E. Bourdonnay, C. Morzadec, O. Fardel, and L. Vernhet Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway J. Immunol., May 1, 2008; 180(9): 6010 - 6017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Alipour, A. J.H. H.M van Oostrom, A. Izraeljan, C. Verseyden, J. M. Collins, K. N. Frayn, T. W.M. Plokker, J. W. F. Elte, and M. Castro Cabezas Leukocyte Activation by Triglyceride-Rich Lipoproteins Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 792 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Jiang, N. Guo, and G. J. Dusting Modulation of Nicotinamide Adenine Dinucleotide Phosphate Oxidase Expression and Function by 3',4'-Dihydroxyflavonol in Phagocytic and Vascular Cells J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 261 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Vendrov, Z. S. Hakim, N. R. Madamanchi, M. Rojas, C. Madamanchi, and M. S. Runge Atherosclerosis Is Attenuated by Limiting Superoxide Generation in Both Macrophages and Vessel Wall Cells Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2714 - 2721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Brizuela, M. Rabano, P. Gangoiti, N. Narbona, J. M. Macarulla, M. Trueba, and A. Gomez-Munoz Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K/PKB and MEK/ERK 1/2 pathways J. Lipid Res., October 1, 2007; 48(10): 2264 - 2274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Gauss, L. K. Nelson-Overton, D. W. Siemsen, Y. Gao, F. R. DeLeo, and M. T. Quinn Role of NF-{kappa}B in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-{alpha} J. Leukoc. Biol., September 1, 2007; 82(3): 729 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Luyendyk, J. D. Piper, M. Tencati, K. V. Reddy, T. Holscher, R. Zhang, J. Luchoomun, X. Chen, W. Min, C. Kunsch, et al. A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1857 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hryniewicz-Jankowska, P. K. Choudhary, and S. R. Goodman Variation in the Monocyte Proteome Experimental Biology and Medicine, July 1, 2007; 232(7): 967 - 976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sugita, H. Sugita, and M. Kaneki Farnesyltransferase Inhibitor, Manumycin A, Prevents Atherosclerosis Development and Reduces Oxidative Stress in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1390 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ikeda, A. Murakami, Y. Fujimura, H. Tachibana, K. Yamada, D. Masuda, K.-i. Hirano, S. Yamashita, and H. Ohigashi Aggregated Ursolic Acid, a Natural Triterpenoid, Induces IL-1beta Release from Murine Peritoneal Macrophages: Role of CD36 J. Immunol., April 15, 2007; 178(8): 4854 - 4864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Figarola, N. Shanmugam, R. Natarajan, and S. Rahbar Anti-Inflammatory Effects of the Advanced Glycation End Product Inhibitor LR-90 in Human Monocytes Diabetes, March 1, 2007; 56(3): 647 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Park, S. S. Choe, A H. Choi, K. H. Kim, M. J. Yoon, T. Suganami, Y. Ogawa, and J. B. Kim Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals Diabetes, November 1, 2006; 55(11): 2939 - 2949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Wang, T. Lee, and S.-E. Chow Role of exercise intensities in oxidized low-density lipoprotein-mediated redox status of monocyte in men J Appl Physiol, September 1, 2006; 101(3): 740 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pignatelli, S. Di Santo, B. Buchetti, V. Sanguigni, A. Brunelli, and F. Violi Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment FASEB J, June 1, 2006; 20(8): 1082 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sagi and R. Fluhr Production of Reactive Oxygen Species by Plant NADPH Oxidases Plant Physiology, June 1, 2006; 141(2): 336 - 340. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Anrather, G. Racchumi, and C. Iadecola NF-{kappa}B Regulates Phagocytic NADPH Oxidase by Inducing the Expression of gp91phox J. Biol. Chem., March 3, 2006; 281(9): 5657 - 5667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Guzik, J. Sadowski, B. Guzik, A. Jopek, B. Kapelak, P. Przybylowski, K. Wierzbicki, R. Korbut, D. G. Harrison, and K. M. Channon Coronary Artery Superoxide Production and Nox Isoform Expression in Human Coronary Artery Disease Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 333 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fortuno, G. San Jose, M. U. Moreno, O. Beloqui, J. Diez, and G. Zalba Phagocytic NADPH Oxidase Overactivity Underlies Oxidative Stress in Metabolic Syndrome Diabetes, January 1, 2006; 55(1): 209 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Jalil, A. Perez, M. P. Ocaranza, J. Bargetto, A. Galaz, and S. Lavandero Increased Aortic NADPH Oxidase Activity in Rats With Genetically High Angiotensin-Converting Enzyme Levels Hypertension, December 1, 2005; 46(6): 1362 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Musiek, L. Gao, G. L. Milne, W. Han, M. B. Everhart, D. Wang, M. G. Backlund, R. N. DuBois, G. Zanoni, G. Vidari, et al. Cyclopentenone Isoprostanes Inhibit the Inflammatory Response in Macrophages J. Biol. Chem., October 21, 2005; 280(42): 35562 - 35570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zalba, O. Beloqui, G. S. Jose, M. U. Moreno, A. Fortuno, and J. Diez NADPH Oxidase-Dependent Superoxide Production Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Atherosclerotic Disease Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1452 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Gauss, P. L. Bunger, T. C. Larson, C. J. Young, L. K. Nelson-Overton, D. W. Siemsen, and M. T. Quinn Identification of a novel tumor necrosis factor {alpha}-responsive region in the NCF2 promoter J. Leukoc. Biol., February 1, 2005; 77(2): 267 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Pagnin, G. Fadini, R. de Toni, A. Tiengo, L. Calo, and A. Avogaro Diabetes Induces p66shc Gene Expression in Human Peripheral Blood Mononuclear Cells: Relationship to Oxidative Stress J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1130 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||