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VASCULAR BIOLOGY
ligands regulate endothelial membrane superoxide production
1Division of Pulmonary and Critical Care Medicine, Veterans Affairs and Emory University Medical Centers, Decatur; and 2Division of Cardiology, Emory University, Atlanta, Georgia
Submitted 24 September 2004 ; accepted in final form 7 December 2004
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ABSTRACT |
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(PPAR-) ligands, either 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, increased endothelial nitric oxide (·NO) release without altering endothelial nitric oxide synthase (eNOS) expression (4). However, the precise molecular mechanisms of PPAR--stimulated endothelial·NO release remain to be defined. Superoxide anion radical (O2–·) combines with ·NO to decrease·NO bioavailability. NADPH oxidase, which produces O2–·, and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), which degrades O2–·, thereby contribute to regulation of endothelial cell·NO metabolism. Therefore, we examined the ability of PPAR- ligands to modulate endothelial O2–· metabolism through alterations in the expression and activity of NADPH oxidase or Cu/Zn-SOD. Treatment with 10 µM 15d-PGJ2 or ciglitazone for 24 h decreased human umbilical vein endothelial cell (HUVEC) membrane NADPH-dependent O2–· production detected with electron spin resonance spectroscopy. Treatment with 15d-PGJ2 or ciglitazone also reduced relative mRNA levels of the NADPH oxidase subunits, nox-1, gp91phox (nox-2), and nox-4, as measured using real-time PCR analysis. Concordantly, Western blot analysis demonstrated that 15d-PGJ2 or ciglitazone decreased nox-2 and nox-4 protein expression. PPAR- ligands also stimulated both activity and expression of Cu/Zn-SOD in HUVEC. These data suggest that in addition to any direct effects on endothelial·NO production, PPAR- ligands enhance endothelial·NO bioavailability, in part by altering endothelial O2–· metabolism through suppression of NADPH oxidase and induction of Cu/Zn-SOD. These findings further elucidate the molecular mechanisms by which PPAR- ligands directly alter vascular endothelial function. reduced nicotinamide adenine dinucleotide phosphate oxidase; copper/zinc superoxide dismutase; nitric oxide; endothelial cells
(PPAR-) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors that regulate genes involved mainly in lipid and glucose metabolism (3, 29). Structurally diverse ligands activate PPAR-, including eicosanoids, 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2), and antidiabetic thiazolidinedione (TZD) drugs, such as troglitazone, ciglitazone, pioglitazone, and rosiglitazone (3, 29). Ligand-induced activation of PPAR- promotes heterodimerization with the retinoid X receptor as well as binding to PPAR response elements (PPRE) in selected target genes, resulting in transcriptional regulation.
Although expressed predominantly in adipose tissue and myeloid cells, PPAR- also is expressed in vascular endothelial and smooth muscle cells. Recent studies have revealed that PPAR- regulates vascular functions unrelated to lipid and carbohydrate metabolism (33). For example, TZD treatment decreased lesion formation in diabetic (8, 30) and nondiabetic (6, 8, 22) animal models of atherosclerosis and reduced arterial wall thickening (26) and blood pressure (27) in patients with diabetes. Troglitazone and rosiglitazone improved endothelium-dependent vasodilation in humans (9) and fatty Zucker rats (34), respectively. Rosiglitazone reduced vascular oxidative stress and improved endothelial dysfunction in a diabetic mouse model in the absence of significant metabolic effects (2). PPAR- activation also suppresses the induction of endothelial adhesion molecules and leukocyte-endothelium interactions (17, 36). The precise mechanisms by which PPAR- ligands modulate the biology of vascular wall cells remain to be defined.
Reactive oxygen species (ROS) and reactive nitrogen species, including superoxide (O2–·), hydrogen peroxide (H2O2), and peroxynitrite, have been implicated in endothelial dysfunction. Within the vascular wall, there are several sources of ROS generation, including NADPH oxidases, cytochrome P-450, xanthine oxidase, uncoupled nitric oxide synthase (NOS), and mitochondria (11). NADPH oxidase, a major source of O2–· generation in the vascular wall (13), is a multicomponent, membrane-associated enzyme that catalyzes the one-electron reduction of oxygen to O2–· using NADPH as the electron donor (11). NADPH oxidase components include the nox homologs and p22phox in the membrane and p47phox, p67phox, and Rac in the cytosol. Among the Nox homologs, human endothelial cells express Nox4 at relatively high levels, gp91phox (Nox2) to a lesser extent, and Nox1 much less abundantly (1, 32). Therefore, NADPH oxidase expression, assembly, and localization are important regulatory steps in endothelial O2–· production.
Intracellular levels of O2–· are controlled not only by the rate of O2–· production but also by the rate of O2–· degradation. Superoxide dismutases (SOD) constitute the major enzymatic mechanism for O2–· degradation and catalyze the conversion of O2–· into H2O2. Three different isoforms of SOD react with O2–· in distinct cellular compartments: cytosolic Cu/Zn-SOD, mitochondrial Mn-SOD, and extracellular SOD. Regulation of endothelial Cu/Zn-SOD activity and expression plays a critical role in protecting against O2–·-mediated reduction of endothelial nitric oxide (·NO) bioavailability. For example, endothelium-dependent vasorelaxation is impaired by inhibition of Cu/Zn-SOD activity and is restored by tiron, a O2–· scavenger (35). Cu/Zn-SOD protein is upregulated in endothelial cells exposed to a variety of stimuli, including anoxia, hyperoxia, H2O2, TNF-
, IL-1 (21), and increased shear stress (16). Collectively, these studies suggest that increased expression of Cu/Zn-SOD may reduce O2–· levels in endothelial cells and thereby augment·NO bioavailability.
Limited evidence suggests that PPAR- ligands reduce endothelial p22phox mRNA and PMA-induced p47phox expression and induce Cu/Zn-SOD mRNA levels (15), indicating that PPAR- ligands could alter endothelial O2–· generation through the regulation of NADPH oxidase and SOD. Because PPAR- ligands enhance endothelial·NO release by a transcriptional mechanism not associated with increased endothelial nitric oxide synthase (eNOS) expression (4), and because·NO bioavailability is regulated in part by O2–·-mediated·NO degradation, we hypothesized that PPAR- ligands might increase·NO bioavailability by suppressing NADPH oxidase as well as enhancing Cu/Zn-SOD activity and expression in endothelial cells. The present study provides novel evidence that PPAR- ligands both suppress endothelial O2–· production and enhance Cu/Zn-SOD-dependent O2–· degradation. In separate studies, we have also examined the effects of PPAR- ligands on eNOS (24). Collectively, these effects provide new insights into mechanisms by which PPAR- ligands enhance endothelial·NO release and bioavailability and confer vascular protection.
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METHODS |
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ligand 15d-PGJ2 (Calbiochem, San Diego, CA) or ciglitazone (Biomol International, Plymouth Meeting, PA). These PPAR- ligand treatment conditions were previously shown to increase endothelial·NO release (4). Superoxide detection. O2–· production was measured by electron spin resonance (ESR) spectroscopy by using the spin probe 1-hydroxy-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CMH; Noxygen Science Transfer & Diagnostics, Denzlingen, Germany). Oxidation of the spin probe CMH by ROS forms stable 3-carboxymethoxyl nitroxide radicals (CM·). Each ESR assay was performed using cells treated with or without polyethylene glycol (PEG)-SOD (50 U/ml) to quantify the SOD-inhibitable formation of CM·.
After treatment with vehicle or one of the PPAR- ligands for 24 h, HUVECs were washed, scraped into ice-cold, Chelex-treated [preincubated for 3 h with 5 g/100 ml of Chelex (Sigma, St. Louis, MO) and filtered] phosphate-buffered saline (PBS; pH 7.4), and centrifuged at 300 g for 6 min. The pellet was resuspended in 1 ml of Chelex-treated PBS containing protease inhibitors (10 µg/ml aprotinin, 0.5 µg/ml leupeptin, 0.7 µg/ml pepstatin, and 0.5 mM phenylmethylsulfonyl fluoride). After being sonicated on ice, membrane fractions were prepared by centrifugation at 28,000 g for 15 min at 4°C. The membrane pellets were resuspended in Chelex-treated PBS with protease inhibitors and 100 µM diethylenetriamine pentaacetic acid to inhibit iron-catalyzed reactions. Protein concentrations were determined using bicinchoninic acid. Cell membranes containing 500 µM CMH and 100 µM NADPH were transferred to a 50-µl capillary tube and analyzed in an ESR spectrometer (Miniscope; Magnettech, Berlin, Germany) by time scan to quantify O2–· production. The ESR settings were as follows: field sweep, 3,355 G; microwave frequency, 9.78 GHz; microwave power, 10 mW; modulation amplitude, 3 G; conversion time, 2,624 ms; time constant, 5,248 ms; and receiver gain, 5 x 102. Signal amplitudes were quantified and normalized to the protein content of the sample.
Western blot analysis. Whole cell lysates (20 µg of protein/lane) derived from HUVECs treated with 10 µM 15d-PGJ2 or ciglitazone were resolved in 4–12% Bis-Tris gels (Invitrogen, Carlsbad, CA), transferred onto a polyvinylidene difluoride membrane (Millipore, Billerica, MA), and probed with primary antibodies specific to nox-2 (gp91phox; provided by Dr. Mark Quinn, Montana State University), nox-4 (provided by Dr. David Lambeth, Emory University), xanthine oxidase (provided by Dr. John Hoidal, University of Utah), Cu/Zn-SOD (Calbiochem), or actin (Santa Cruz Biotechnology, Santa Cruz, CA). After being washed, membranes were incubated with horseradish peroxidase-conjugated secondary antibody (Jackson ImmunoResearch Laboratories, West Grove, PA). Immunodetection was performed using a chemiluminescence method (SuperSignal; Pierce Biotechnology, Rockford, IL), and relative immunoreactive levels of proteins were quantified using the ChemiDoc XRS imaging system and Quantity One software, version 4.5 (Bio-Rad Laboratories, Hercules, CA). All data were normalized to the actin content of the same sample.
Quantitative real-time PCR. Real-time PCR was performed to quantify mRNA levels of Nox1, Nox2 (gp91phox), and Nox4. Briefly, isolation of total RNA from HUVEC monolayers was performed according to the manufacturer's protocol (RNeasy Mini kit; Qiagen, Valencia, CA). Total RNA (2.5 µg) was reverse transcribed using random primers and a SuperScript II kit (Invitrogen). The first-strand cDNA was purified using a microbiospin 30 column (Bio-Rad Laboratories) in Tris buffer and then stored at –20°C until used. Endothelial cDNA was amplified using a LightCycler real-time thermocycler (Roche Diagnostics, Indianapolis, IN). The mRNA copy numbers were calculated from standard curves generated with human Nox1, Nox2, Nox4, and 18S templates. None of the treatment conditions had a significant effect on 18S expression. The plasmids for these standards were generously provided by Dr. David Lambeth (Emory University).
Cu/Zn-SOD activity. SOD activity was determined spectrophotometrically by measuring sample-mediated inhibition of xanthine oxidase-dependent O2–· production (Superoxide Dismutase Assay Kit; Cayman Chemical, Ann Arbor, MI) using 96-well plates. Briefly, cells were harvested by scraping and centrifuged at 1,000 g for 10 min. Cell pellets were resuspended in ice-cold lysis buffer (20 mM HEPES, pH 7.2, containing 1 mM EGTA, 210 mM mannitol, and 70 mM sucrose) and sonicated. After centrifugation of lysates at 1,500 g for 5 min at 4°C, supernatants were centrifugated again at 10,000 g for 15 min at 4°C, resulting in the separation of mitochondrial Mn-SOD into the pellet and cytosolic Cu/Zn-SOD in the remaining supernatant. After the addition of supernatant and a chromogenic tetrazolium salt (free radical detector) onto 96-well plates, xanthine oxidase was added as an enzymatic source of O2–·. The samples were incubated for 20 min at room temperature, and endpoint measurements were performed at 450 nm. One unit of SOD is defined as the amount of enzyme needed to exhibit 50% dismutation of O2–·.
Statistical analysis. For all experiments, statistical analysis was performed using one-way ANOVA, followed by post hoc analysis using the Student-Newman-Keuls test to detect differences between experimental groups. A value of P < 0.05 was considered statistically significant.
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RESULTS |
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ligands inhibit endothelial superoxide production.
ESR spectroscopy was performed to determine whether the natural PPAR- ligand, 15d-PGJ2, or the synthetic PPAR- agonist, ciglitazone, regulated membrane-associated, NADPH-dependent O2–· production by NADPH oxidase. CMH was used as a O2–·-specific spin probe, and PEG-SOD-inhibitable formation of CM· was determined. Compared with control, treatment with 10 µM 15d-PGJ2 or ciglitazone for 24 h significantly decreased endothelial O2–· production by 
50% (Fig. 1), indicating that PPAR- ligands decreased HUVEC NADPH oxidase activity.
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ligands suppress Nox homolog mRNA and protein expression in HUVEC.
As previously reported, human endothelial cells express multiple Nox homologs (1, 32). Table 1 demonstrates that HUVEC expressed Nox4 to a greater degree than Nox2, and Nox1 to a lesser extent. As shown in Fig. 2, PPAR- ligands suppressed HUVEC Nox homolog expression. Ciglitazone decreased HUVEC Nox1 mRNA levels to 52% of control values, whereas 15d-PGJ2 decreased Nox1 mRNA by 20% (Fig. 2A). Similarly, treatment with either 15d-PGJ2 or ciglitazone reduced Nox2 mRNA levels up to 85% from that of the control group (Fig. 2B). Treatment with 15d-PGJ2 or ciglitazone also decreased Nox4 mRNA levels by 40 and 30%, respectively (Fig. 2C). These PPAR- ligand-induced reductions in Nox mRNA expression were associated with corresponding reductions in protein expression. Treatment with 15d-PGJ2 decreased Nox2 and Nox4 protein expression, whereas ciglitazone had no significant effect on protein expression (Fig. 3). Immunoblotting whole cell lysates for nox homologs reveals protein subunits with varying degrees of glycosylation; for example, Nox2 appeared at 90-kDa band as previously reported (23). The Nox4 antibody revealed bands at 80 kDa and at 65 kDa, both of which were blocked by preincubating the Nox4 antibody with excess antigenic peptide (12). At present, it is not clear whether these bands represent the same protein with varying degrees of glycosylation as reported for Nox2. However, relative to control, PPAR- ligands suppressed both the 80-kDa and 65-kDa bands to a similar extent, consistent with the suppression of mRNA transcripts shown in Fig. 2. The impact of PPAR- ligands on O2–·-generating enzymes appeared limited to NADPH oxidase, because neither 15d-PGJ2 nor ciglitazone altered HUVEC xanthine oxidase expression (Fig. 4), another important source of O2–· production in endothelial cells (25).
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ligands enhance expression and activity of Cu/Zn-SOD.
On the basis of a previous report that PPAR- ligands increased Cu/Zn-SOD mRNA in endothelial cells (15), we investigated the ability of PPAR- ligands to alter the protein levels and activity of Cu/Zn-SOD as an additional mechanism that potentially reduces O2–· levels and leads to increased·NO bioavailability. Cu/Zn-SOD protein expression was significantly enhanced in HUVECs treated with 10 µM 15d-PGJ2 (175 ± 20%) or ciglitazone (126 ± 24%) compared with control (Fig. 5A). In addition, Cu/Zn-SOD activity was also increased approximately twofold after treatment with either PPAR- ligand (Fig. 5B).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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ligands enhanced endothelial·NO release without altering eNOS expression, providing a potential mechanism for the vascular protective effects of PPAR- ligands, independent of their metabolic effects. Because the precise mechanisms by which PPAR- ligands alter endothelial·NO release are not fully defined, the present study focused on endothelial O2–· metabolism as an important regulatory mechanism for endothelial·NO release. Our results indicate that PPAR- ligands may improve endothelial·NO release by simultaneously suppressing O2–· generation and enhancing its degradation, thereby reducing its ability to inhibit endothelial·NO release.
Each of the PPAR- ligands, 15d-PGJ2 and ciglitazone, suppressed NADPH-driven, membrane-derived O2–· generation, consistent with inhibition of NADPH oxidase activity. This finding is consistent with previous reports that PPAR- ligands suppress vascular oxidative stress. For example, troglitazone was previously reported to decrease p22phox mRNA and p47phox protein levels in PMA-stimulated human aortic endothelial cells (15), and rosiglitazone reportedly decreased NADPH oxidase activity in a rat model of hypertension (14) and in a mouse model of diabetes (2). The present study extends findings of these previous studies by demonstrating that 15d-PGJ2 and ciglitazone, two structurally unrelated PPAR- ligands, each decreased mRNA and protein expression of Nox homologs in vascular endothelial cells. Both ligands suppressed Nox homolog mRNA to a greater extent than the corresponding protein, suggesting that maximal suppression of Nox protein may be delayed because of the potentially long half-life of previously transcribed protein. Ciglitazone had a slightly greater effect than 15d-PGJ2 on Nox1 mRNA level. In contrast, 15d-PGJ2 reduced Nox2 and Nox4 protein expression to a greater degree than ciglitazone did. Unfortunately, available Nox1 antibodies did not permit convincing analysis of PPAR- ligand effects on protein levels of this Nox homolog, which may be attributable in part to its less robust expression in HUVECs (Table 1). Differences in the effects of individual PPAR- ligands on Nox expression may relate to differences in the binding affinity of these ligands for the PPAR- receptor (18, 19, 31). In addition, different PPAR- ligands elicit differential conformational alterations of the PPAR- receptor, leading to the recruitment of discrete coactivator and corepressor molecules that result in overlapping but varying patterns of gene expression (5, 28). Nonetheless, 15d-PGJ2 and ciglitazone caused comparable reductions in NADPH oxidase activity, suggesting the potential for suppression of additional NADPH oxidase subunits, an area of active investigation in our laboratory.
Because altered Cu/Zn-SOD activity and expression as well as altered NADPH oxidase-dependent O2–· production play an important role in regulating·NO bioavailability, we examined the relationship between PPAR- ligands and Cu/Zn-SOD. We found that PPAR- ligands stimulated Cu/Zn-SOD activity and expression, extending the findings of a previous report that PPAR- and PPAR- ligands increased endothelial Cu/Zn-SOD mRNA levels (15). Although the molecular basis for PPAR- ligand-induced increases in SOD expression has not been defined, the identification of a functional PPRE in the Cu/Zn-SOD promoter suggests that Cu/Zn-SOD gene expression may be stimulated directly by PPAR- activation (10, 20, 37). These previous results, coupled with the findings of the present study, demonstrate that PPAR- activation enhances vascular endothelial SOD activity.
We postulate that PPAR- ligands directly activate a program of gene expression in vascular endothelial cells that results in increased·NO bioavailability (Fig. 6). PPAR- ligands stimulate endothelial·NO release (4, 7), in part by modulating posttranslational mechanisms of eNOS regulation, including eNOS phosphorylation and eNOS-protein interactions. For example, specific PPAR- ligands increased phosphorylation of eNOS Ser116 and Ser1177. PPAR- ligands also increased the association of eNOS with heat shock protein 90 and decreased the association of eNOS with caveolin-1 (J. A. Polikaudriotis, L. J. Mazzella, H. L. Rupnow, and C. M. Hart, unpublished observations). The present study extends these findings by demonstrating that PPAR- ligands suppress nox mRNA and protein expression and activity as well as enhance the activity and expression of Cu/Zn-SOD (2, 15). Collectively, these findings indicate that PPAR- ligands coordinately regulate the balance between endothelial·NO and O2–· production in vascular endothelial cells.
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ligand-induced alterations in O2–· metabolism and enhanced·NO bioavailability that could reduce endothelial dysfunction and its attendant vascular disease. Ongoing studies in our laboratories will determine whether these in vitro observations occur in vivo and whether PPAR- ligands suppress O2–· generation stimulated by inflammatory mediators. If so, these studies could further clarify the vascular protective effects of PPAR- ligands and stimulate the development of novel strategies for the prevention or treatment of vascular disease associated with endothelial dysfunction. |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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 N. Bashan, J. Kovsan, I. Kachko, H. Ovadia, and A. Rudich Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species Physiol Rev, January 1, 2009; 89(1): 27 - 71. [Abstract] [Full Text] [PDF]
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Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2436 - H2446. [Abstract] [Full Text] [PDF]
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 M. Collino, N. S.A. Patel, and C. Thiemermann Review: PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 179 - 197. [Abstract] [PDF]
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 S. Z. Duan, M. G. Usher, and R. M. Mortensen Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature Circ. Res., February 15, 2008; 102(3): 283 - 294. [Abstract] [Full Text] [PDF]
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G. Ceolotto, A. Gallo, I. Papparella, L. Franco, E. Murphy, E. Iori, E. Pagnin, G. P. Fadini, M. Albiero, A. Semplicini, et al. Rosiglitazone Reduces Glucose-Induced Oxidative Stress Mediated by NAD(P)H Oxidase via AMPK-Dependent Mechanism Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2627 - 2633. [Abstract] [Full Text] [PDF]
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G. Ding, M. Fu, Q. Qin, W. Lewis, H. W. Kim, T. Fukai, M. Bacanamwo, Y. E. Chen, M. D. Schneider, D. J. Mangelsdorf, et al. Cardiac peroxisome proliferator-activated receptor {delta} is essential in protecting cardiomyocytes from oxidative damage Cardiovasc Res, November 1, 2007; 76(2): 269 - 279. [Abstract] [Full Text] [PDF]
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G. Zalba, A. Fortuno, J. Orbe, G. San Jose, M. U. Moreno, M. Belzunce, J. A. Rodriguez, O. Beloqui, J. A. Paramo, and J. Diez Phagocytic NADPH Oxidase-Dependent Superoxide Production Stimulates Matrix Metalloproteinase-9: Implications for Human Atherosclerosis Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 587 - 593. [Abstract] [Full Text] [PDF]
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 A. von Knethen, M. Soller, N. Tzieply, A. Weigert, A. M. Johann, C. Jennewein, R. Kohl, and B. Brune PPAR{gamma}1 attenuates cytosol to membrane translocation of PKC{alpha} to desensitize monocytes/macrophages J. Cell Biol., February 26, 2007; 176(5): 681 - 694. [Abstract] [Full Text] [PDF]
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 J. D. Brown and J. Plutzky Peroxisome Proliferator Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets Circulation, January 30, 2007; 115(4): 518 - 533. [Abstract] [Full Text] [PDF]
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K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
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Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1158 - H1169. [Abstract] [Full Text] [PDF]
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P. Rocic, B. Rezk, and P. A. Lucchesi PPAR-{gamma} agonists decrease hyperhomcysteinemia and cardiac dysfunction: new hope for ailing diabetic hearts? Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H26 - H28. [Full Text] [PDF]
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