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  • 1
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    Online Resource
    AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase
    Ovid Technologies (Wolters Kluwer Health) ; 2003
    In:  Circulation Vol. 107, No. 12 ( 2003-04), p. 1632-1639
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 12 ( 2003-04), p. 1632-1639
    Abstract: Background— We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT 1 -AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT 1 -AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-κB (NF-κB) activation. Methods and Results— We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT 1 -AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT 1 -AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT 1 -AA lead to NF-κB activation in VSMC and trophoblasts. AT 1 -AA activated NF-κB. Inhibitor-κBα (I-κBα) expression was reduced in response to AT 1 -AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-κB activation. VSMC from p47phox−/− mice showed markedly reduced ROS generation and NF-κB activation in response to Ang II and AT1-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-κB was activated and I-κBα reduced in placentas from preeclamptic women. Conclusions— NADPH oxidase is potentially an important source of ROS that may upregulate NF-κB in preeclampsia. We suggest that AT 1 -AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000058200.90059.B1
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 1466401-X
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  • 2
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    Amelioration of Angiotensin Ii-Induced Cardiac Injury by Hmg-Coa Reductase Inhibition
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Hypertension Vol. 36, No. suppl_1 ( 2000-10), p. 683-683
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2000-10), p. 683-683
    Abstract: 32 HMG-CoA reductase inhibitors have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II-dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury. We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from week 4 to 7 with cerivastatin (0.5 mg/kg/d by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and RT-PCR techniques. Compared to control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I and IV deposition. Total plasma cholesterol was not different between the groups. Immunohistochemical analysis showed increased expression of basic fibroblast growth factor (b-FGF), IL-6, and the NF-κB subunit p65 in the media of dTGR, which was markedly reduced by cerivastatin. b-FGF mRNA in the left ventricle was also significantly reduced. The transcription factors NF-κB and AP-1 were substantially less activated in the left ventricle. These results suggest that statins ameliorate Ang II-induced hypertension, cardiac hypertrophy, and remodeling, independent of cholesterol reduction. They suggest that statins interfere with Ang II-induced signaling and transcription factor activation, thereby ameliorating end-organ damage.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.36.suppl_1.683-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 2094210-2
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  • 3
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    NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Hypertension Vol. 35, No. 1 ( 2000-01), p. 193-201
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    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 1 ( 2000-01), p. 193-201
    Abstract: Abstract —We recently reported that the activation of nuclear factor-κB (NF-κB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-κB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-κB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162±8 versus 190±7 mm Hg; P =0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90±0.1 versus 5.77±0.1 mg/g; P 〈 0.001). PDTC reduced 24-hour albuminuria by 〉 95% (2.5±0.8 versus 57.1±8.7 mg/d; P 〈 0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-κB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c- fos and c- jun mRNA expression. PDTC treatment reduced c- fos but not c- jun mRNA. Immunohistochemistry showed increased p65 NF-κB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-κB–dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-κB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/01.HYP.35.1.193
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 2094210-2
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  • 4
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    AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Circulation Vol. 101, No. 20 ( 2000-05-23), p. 2382-2387
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 101, No. 20 ( 2000-05-23), p. 2382-2387
    Abstract: Background —We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT 1 -AA) directed at the AT 1 receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT 1 -AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT 1 -AA cause vascular smooth muscle cells (VSMC) to express TF. Methods and Results —IgG from preeclamptic patients containing AT 1 -AA was purified with anti-human IgG columns. AT 1 -AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT 1 receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT 1 -AA specificity by coimmunoprecipitating the AT 1 receptor with AT 1 -AA but not with nonspecific IgG. Angiotensin (Ang) II and AT 1 -AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT 1 -AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect. Conclusions —We conclude that AT 1 -AA and Ang II both stimulate the AT 1 receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT 1 -AA on human cells that could contribute to the pathogenesis of preeclampsia.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.101.20.2382
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1466401-X
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  • 5
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    Cytochrome P450-Dependent Eicosapentaenoic Acid Metabolites Are Novel BK Channel Activators
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Hypertension Vol. 39, No. 2 ( 2002-02), p. 609-613
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 2 ( 2002-02), p. 609-613
    Abstract: P450-dependent arachidonic acid (AA) metabolites regulate arterial tone by modulating calcium-activated (BK) potassium channels in vascular smooth muscle cells (VSMC). Because eicosapentaenoic acid (EPA) has been reported to improve vascular function, we tested the hypothesis that P450-dependent epoxygenation of EPA produces alternative vasoactive compounds. We synthesized the 5 regioisomeric epoxyeicosattrienoic acids (EETeTr) and examined them for effects on K + currents in rat cerebral artery VSMCs with the patch-clamp technique. 11(R),12(S)-epoxyeicosatrienoic acid (50 nmol/L) was used for comparison and stimulated K + currents 6-fold at +60 mV. However, 17(R),18(S)-EETeTr elicited a more than 14-fold increase. 17(S),18(R)-EET and the remaining four regioisomers were inactive. The effect of 17(R),18(S)-EETeTr was blocked by tetraethylammonium but not by 4-aminopyridine. VSMCs expressed P450s 4A1 and 4A3. Recombinant P450 4A1 hydroxylated EPA at C-19 and C-20 and epoxygenated the 17,18-double bond, yielding the R, S- and S, R-enantiomers in a ratio of 64:36. We conclude that 17(R),18(S)-EETeTr represents a novel, potent activator of BK potassium channels. Furthermore, this metabolite can be directly produced in VSMCs. We suggest that 17(R),18(S)-EETeTr may function as an important hyperpolarizing factor, particularly with EPA-rich diets.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hy0202.103293
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 2094210-2
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  • 6
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    Dexamethasone Inhibits Nf-κB, P22phox, and Protects Against Angiotensin Ii-Induced Renal Damage
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Hypertension Vol. 36, No. suppl_1 ( 2000-10), p. 723-723
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2000-10), p. 723-723
    Abstract: P167 We recently reported that NF-κB activation promotes inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). We now tested the hypothesis that dexamethasone (DEX) inhibits NF-κB and ameliorates renal and cardiac end-organ damage. The dTGR feature moderate hypertension, severe renal, and cardiac damage, as well as over 50% mortality at 7 weeks. Immunohistochemical analysis shows increased infiltration of monocytes and T-cells. Electrophoretic mobility shift assay showed increased NF-κB DNA binding activity in heart and kidney of dTGR. One-week treatment with DEX (1 mg/kg/d i.p.) initially increased blood pressure at week 5, compared to dTGR (191±2 vs.152±6 mm Hg, p 〈 0.01), whereas blood pressure was not different at week 7 (193±15 vs. 182±8 mm Hg, p=0.8). However, DEX reduced 24 h albuminuria by 85 % (2.7±0.5 vs. 18.0±3.4 mg/d, p 〈 0.001) and prevented mortality completely. Vasculopathy was ameliorated in kidney and heart and perivascular fibrosis was reduced. DEX inhibited NF-κB DNA-binding activity and also the NF-κB-regulated adhesion molecule ICAM-1. We also studied localization of NADPH subunit p22phox. Immunostaining of p22phox was detected in the endothelium and also colocalized with monocytes. DEX reduced both infiltration of cells and p22phox expression. Thus, these results demonstrate that DEX suppresses NF-κB binding activity, p22phox expression of infiltrated cells, inflammation, and protects against angiotensin II-induced end-organ damage, all without blood pressure reduction.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.36.suppl_1.723-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 2094210-2
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