Published online before print June 21, 2007, doi: 10.1161/CIRCRESAHA.107.150474
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© 2007 American Heart Association, Inc.
Molecular Medicine |
Vascular Endothelial Cell–Specific NF-
B Suppression Attenuates Hypertension-Induced Renal Damage
From the Medical Faculty of the Charité (N.H., R.D., M.W., R.D., F.C.L., D.N.M.), Franz Volhard Clinic, HELIOS Klinikum-Berlin; the Max-Delbrück-Center for Molecular Medicine (R.S.-U., F.Q., M.O., V.G., F.C.L., C.S., D.N.M.), Berlin-Buch; and the Medical School of Hannover (J.-K.P.), Hannover, Germany.
Correspondence to Ruth Schmidt-Ullrich, PhD, Max-Delbrück-Center, Robert-Rossle Street 50, 13125 Berlin-Buch, Germany. E-mail rschmidt{at}mdc-berlin.de
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Abstract |
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Nuclear factor kappa B (NF-
B) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell–specific NF-B suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell–restricted NF-B super-repressor IB
N (Tie-1-N mice) overexpression. We confirmed cell-specific IBN expression and reduced NF-B activity after TNF- stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-L-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-N and control mice. In contrast to control mice, Tie-1-N mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-B targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-B activation and hypertension-induced renal damage. We conclude that in vivo NF-B suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.
Key Words: hypertension • endothelium • NF-B • target-organ damage
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Introduction |
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Hypertension is a risk factor for target-organ damage such as cardiac and renal disease.1 Endothelial cell injury initiates adhesion molecule and chemokine expression promoting inflammation that contributes to the pathogenesis of hypertension-induced target organ damage.2–5 Patients with severe hypertension and target-organ damage often show elevated angiotensin (Ang) II levels and reduced nitric oxide (NO) production. Ang II signaling blockade reduces blood pressure and blunts the development and progression of vascular disease in small and large vessels in experimental animal models and in humans. Ang II also elicits an inflammatory response in both endothelial cells6 and vascular smooth muscle cells.7,8 Numerous in vitro and in vivo studies demonstrated that Ang II activates the nuclear factor kappa B (NF-
B), a major transcription factor in mediating inflammation and innate immunity.4,6–8 In resting cells, NF-B resides inactive in the cytoplasm by forming complexes with the inhibitor of B (IB) proteins. Exposure to extracellular stimuli like TNF-, IL-1, reactive oxygen species, Ang II, and numerous other activators leads to rapid phosphorylation, site-specific ubiquitination, and subsequent degradation of the IB proteins by the 26S proteasome.9 The resulting free NF-B molecules translocate to the nucleus and regulate target gene expression. The targets include genes involved in the control of cell proliferation, apoptosis, innate, and adaptive immune response.10,11 NF-B and inflammation play an important role in the development of the target organ damage.4,12–17 However, inhibition of NF-B signaling could also be detrimental.18,19 Furthermore, the ideal site for NF-B inhibition in the vessel wall is unknown. To address the role of NF-B in the endothelium in hypertension-induced renal damage, we used the Cre/lox technique to generate a novel mouse model with endothelial cell–restricted expression of the human NF-B super-repressor IBN.14,20 |
Materials and Methods |
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Mice
For endothelial cell–restricted super-repressor I
BN overexpression, mice carrying loxP-flanked alleles encoding for the human IBN (loxP-N) were crossed with Cre knock-in mice expressing the Cre recombinase under the control of endothelial-specific Tie-1 promoter. Tie-1-Cre mice were a gift from Dr Erika Gustafsson.21 The loxP-N mice were described previously.14,20 The Tie-1-Cre knock-in mediates excision of loxP-flanked sequences in renal, cardiac, pulmonary, and aortic endothelial cells.21 The double knock-in mice were designated Tie-1-N. All mice were bred on a C57Bl/6 background for more than 7 generations. The Berlin Animal Review Board approved all protocols (Reg. 0135/01 and G 0261/02).
Ang II/L-NAME Mouse Model
Eight-week-old control mice (single transgenic Tie-1-Cre and loxP-N, wild-type C57BL/6 mice) and Tie-1-N double transgenic mice (n
21 for each group) received the NO synthase inhibitor N(omega)-nitro-L-arginine-methyl-ester (L-NAME). L-NAME was given at 0.1 mg·mL–1 in the drinking water. Ang II (1.0 mg·kg–1·day–1) was infused via ALZET mini pumps. The animals were fed a high-sodium diet (1% sodium in the chow) for 14 days.22 Because C57BL/6, Tie-1-Cre, and loxP-N mice showed no differences in renal histology, albuminuria, cell infiltration, and gene expression, these groups were combined and termed controls. We measured 24-hour mouse urinary albumin by ELISA (CellTrend, Germany). Animals were killed on day 14 under ether anesthesia. Hearts and kidneys were washed, weighed, harvested, and stored until analysis.
Telemetric Mean Arterial Pressure Measurements
Telemetry system and Dataquest ART 2.0 software from Data Sciences International were used to measure intracarotid blood pressure in 4 to 5 mice per group. Briefly, a telemetry probe catheter (TA11-PA40; Data Sciences International) was inserted into the surgically exposed carotid artery.23 After surgery, all mice were allowed at least 7 days to recover. Before Ang II/L-NAME treatment, baseline values were continuously recorded for 3 days and averaged. Days 10 to 12 after Ang II/L-NAME treatment, blood pressure and heart rate were recorded and statistically analyzed. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were sampled at 100 Hz. Mean arterial pressure (MAP) was calculated as follows: MAP=DBP+(SBP-DBP)/3.
Immunohistochemistry and In Situ Hybridization
Ice-cold acetone-fixed cryosections (6 µm) were stained by indirect immunofluorescence techniques as described earlier.17 The sections were incubated with the following antibodies: anti-F4/80, anti-CD4 (both serotec, UK), anti-CD3, anti-CD8 (both BD Bioscience, Germany), anti-collagen III (Fitzgerald, Mass), anti-VCAM-1 (SantaCruz, Germany), anti-ICAM-1 (Dianova, Germany), anti-p65 (Abcam, UK), and anti-TNF- (SantaCruz, Germany). For histology and in situ hybridization, paraffin sections were used. Masson trichrome stain was performed by clinical routine protocol. Semiquantification of tubular damage was performed as described in online methods. P65 semiquantification was evaluated with a scoring system1–5 based on the number of p65+ nuclei. Paraffin sections were also stained with sirius red to evaluate the degree of fibrosis. In situ hybridization was performed as described earlier.24 The murine IB (nt 1 to 1091, U36277/NM010907) cDNA was used. Sections were counterstained with 0.01% PyroninG and mounted with Entellan (Merck). All pictures were taken with a Zeiss Axioplan 2 Imaging microscope/Axiophot camera.
Endothelial Cell Culture
Murine lung and aortic endothelial cells were isolated with Dynabeads coated with anti–platelet-endothelial cell adhesion molecule-1 or anti–ICAM-2 monoclonal antibody as described previously.25,26 Endothelial cells were cultured with DMEM supplemented with 20% FBS, heparin, endothelial cell growth factor, nonessential amino acids, and antibiotics.
Immunoblotting and Electrophoretic Mobility Shift Assay
Endothelial cells were stimulated with TNF- (20 ng/mL; Biomol, Germany) as indicated. Whole cell extracts were prepared as described earlier.27 electrophoretic mobility shift assay (EMSA) was performed with 5 µg whole cell protein as described previously.27 For immunoblotting, 20 µg whole cell lysate protein was used and revealed with an IB antibody (Santa Cruz, Germany).
Quantitative TaqMan RT-PCR
Total kidney RNA was isolated using the TRIZOL protocol; RNA from cells with the RNeasy kit (Qiagen, Germany). TaqMan RT-PCR by SYBR Green analysis was performed as described earlier.28 ICAM-1 and VCAM-1 mRNA quantities were analyzed in duplicate. For quantification, the target sequences were normalized in relation to the mouse GAPDH product (Clonetech, Germany). Biotez (Berlin, Germany) synthesized the primers. The sequences are listed in the online method section.
Statistical Analysis
Differences between experimental groups were analyzed by use of adjusted student t test or ANOVA for repeated measures, as appropriate. Data are reported as mean±SEM. Values of P<0.05 were considered significant.
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Results |
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Generation of Mice with Endothelial-Specific NF-
B InhibitionThe breeding scheme of floxed I
BN (loxP-N) mice and heterozygous Tie-1–Cre knock-in mice to generate mice with endothelial cell–restricted IBN expression, namely Tie-1-N mice, is given (Figure 1). IBN lacks the destruction box containing the phosphorylation and ubiquitination sites and acts as a super-repressor of NF-B activity (supplemental Figure I, available online at http://circres.ahajournals.org). To confirm the correct functioning of the Tie-1–Cre line, Tie-1–Cre mice were mated with ROSA26Rflox/flox reporter mice and endothelial cell–specific LacZ staining pattern in the aorta was observed (data not shown). These results agree with the previous description of the Tie-1-directed Cre expression.21,29 Recombination in Tie-1-N mice was verified by immunoblot analysis of whole cell extracts from isolated primary endothelial cells (Figure 2A). IBN lacks the N-terminal 70 amino acids and thus runs at a smaller molecular weight range than endogenous IB (Figure 2A). The efficiency of NF-B inhibition in Tie-1-N was confirmed by EMSA (Figure 2B and 2C). After TNF- stimulation, cultured endothelial cells from Tie-1-N showed a reduced NF-B DNA-binding activity, compared with wild-type control cells (Figure 2C). Residual induced NF-B activity was most likely derived from nonrecombinant endothelial cells, because the Cre recombinase does not function 100%. Excision of loxP sites by Tie-1 promoter-induced Cre is estimated to take place in 70 and 95% of endothelial cells depending on the organ.21 Cultured wild-type endothelial cells may grow at a faster rate and eventually outnumber Tie-1-N endothelial cells. Interestingly, in situ hybridization (Figure 2D) using a murine anti-sense RNA probe of the bona fide NF-B target gene IB clearly demonstrated that hypertensive control mice with severe renal damage showed strong IB signals in various substructures of the kidney, namely blood vessels, tubules, and glomeruli. The increased IB expression at these sites can be used as a direct read-out for NF-B activity. As expected, in all these structures we observed significantly less upregulation of IB expression in Tie-1-N mice and in sham-controls (Figure 2D). This result already suggests that NF-B activity in endothelial cells has a direct effect on NF-B activation in the surrounding structures such as tubules and glomeruli. We analyzed nuclear p65 immunoreactivity as a marker for NF-B activation. Vascular endothelial cells from Ang II/L-NAME-treated control mice often showed p65+ nuclei, whereas only a few endothelial cells were positive in from Ang II/L-NAME–treated Tie-1-N mice (supplemental Figure IIA). Tubular p65 nuclei were significantly less frequent in mice with suppressed NF-B signaling compared with Ang II/L-NAME–treated control mice, but still (supplemental Figure IIB and IIC).
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NF-B Activation Promotes Hypertension-Induced Renal Damage
Blood pressure recordings revealed that control mice and Tie-1-N mice were normotensive before Ang II/L-NAME treatment (106±1 mm Hg versus 103±1 mm Hg, respectively; Figure 3A). Chronic Ang II/L-NAME administration raised the mean arterial blood pressure (MAP) by 40 mm Hg. There was no difference in MAP between both groups (143±5 mm Hg for control and 143±4 mm Hg for Tie-1-N; Figure 3A). Baseline urinary albumin excretion was also similar between both groups (Figure 3B). However, after Ang II/L-NAME treatment, albuminuria was significantly higher in control mice compared with Tie-1-N mice (6876±1058 versus 3022±737 µg/d, respectively, P<0.05; Figure 3B).
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Masson trichrome stain of kidney tissue showed that Ang II/L-NAME–treated control mice had severe tubular and vascular damage with increased matrix production, compared with control mice (Figure 4A). Semiquantification of tubular damage supported this result (Figure 4B). Ang II/L-NAME–treated Tie-1-N mice also showed histological changes. Nevertheless, matrix formation and tubular damage were significantly less pronounced in mice with suppressed NF-B signaling compared with Ang II/L-NAME–treated control mice (Figure 4A and 4B). Sirius red stains confirmed a significant reduction of perivascular and interstitial fibrosis in Ang II/L-NAME–treated Tie-1-N mice (Figure 4C). Vascular damage was less pronounced in Ang II/L-NAME–treated Tie-1-N compared with control mice (supplemental Figure IIIA). Suppressed NF-B activity only protected glomeruli to a minor degree. Glomerular collagen III deposition was partially reduced in Ang II/L-NAME–treated Tie-1-N mice (supplemental Figure IIIB).
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NF-B Drives Renal TNF-, VCAM-1, and ICAM-1 Expression in Hypertensive Mice
TNF- expression was increased in damaged glomeruli, tubules, and the vessel wall from Ang II/L-NAME–treated controls, significantly reduced in Ang II/L-NAME–treated Tie-1-N mice, and hardly or not expressed in sham controls (Figure 5). RT-PCR analysis revealed that after Ang II/L-NAME treatment renal VCAM-1 (Figure 6A) and ICAM-1 (Figure 6B) expression was significantly increased in control mice, compared with Tie-1-N mice. Nevertheless, both groups showed significantly increased adhesion molecule expression, compared with untreated normotensive sham-control mice (Figure 6A and 6B). Immunohistological analysis of renal VCAM-1 (Figure 6C) and ICAM-1 (Figure 6D) confirmed our RT-PCR results. Interestingly, we observed different expression patterns of VCAM-1 and ICAM-1 immunoreactivity in large or medium arteries, small arterioles, and capillaries. Large and medium arteries, as well as capillaries of treated Tie-1-N mice showed a significantly reduced adhesion molecule expression compared with controls. However, arterioles showed the same staining intensity as treated controls (data not shown). This result suggests insufficient Cre recombination in arterioles. ICAM-1 was also expressed constitutively in the interstitium. However, Ang II/L-NAME–treated Tie-1-N mice showed a significantly reduced renal ICAM-1 immunoreactivity in the interstitium, glomerular bed (Figure 6D upper panel), and the vessel wall (Figure 6D lower panel) compared with Ang II/L-NAME–treated controls.
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Renal Inflammatory Cell Infiltration Is Controlled by NF-B
Because of the increased VCAM-1 and ICAM-1 expression in Ang II/L-NAME-treated animals, we analyzed immune cell infiltration in our treated mouse models. Using an anti-CD3 antibody, elevated T-cell infiltration is seen in kidneys of treated control animals and to a lesser degree in Tie-1-N animals (Figure 7A). The 2 T cell subpopulations that included CD4+ (helper) and CD8+ (cytotoxic) T-cells, as well as macrophages (F4/80+ cells), were primarily located around blood vessels and to a lesser extent within the interstitium. We quantified infiltrating monocytes/macrophages, T cells (CD3+, CD4+), and CD8+ T-cell subpopulations in stained renal sections (Figure 7B through 7E). We observed partially diminished renal immune cell infiltration in Ang II/L-NAME–treated-Tie-1-N compared with Ang II/L-NAME–treated control mice (Figure 7B through 7E). Nevertheless, cell infiltration was still significantly increased in treated Tie-1-N mice, compared with untreated sham-controls (Figure 7B through 7E).
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Discussion |
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The surprising finding is that endothelial-specific NF-
B suppression suffices to ameliorate Ang II/L-NAME hypertension-induced renal damage. The results demonstrate that inhibition of NF-B signaling in a single cell type is able to reduce renal tubular, vascular, and to a minor extent also glomerular damage. Endothelial NF-B inhibition did not affect the development of hypertension, indicating that the renal protection was blood pressure–independent. Our study provides the first in vivo evidence that specific endothelial NF-B inhibition results in a diminished upregulation of several proinflammatory NF-B target genes including VCAM-1 and ICAM-1 and reduces renal inflammation.
Hypertension is a major risk factor for cardiovascular events. Nevertheless, high blood pressure is not a unique factor in the pathogenesis of target organ damage. We reported earlier that dexamethasone inhibited NF-B activity and prevented renal damage in an Ang II–dependent rat model despite blood pressures exceeding 200 mm Hg.30 In the present study, Ang II/L-NAME–treated controls and Tie-1-N mice were severely hypertensive and both developed renal damage. Nevertheless, endothelial-specific NF-B suppression protected Tie-1-N mice to a significant extent.
NF-B plays an important role in the pathogenesis of cardiovascular disease. Cardiac NF-B inhibition by a decoy technique reduced the extent of myocardial infarction after reperfusion.31 In renal allografts, pretreatment of donor kidneys with NF-B decoys led to reduced NF-B activity and expression of VCAM-1 leading to reduced cell infiltration.32 Boyle et al showed that treatment with pyrrolidine dithiocarbamate (PDTC), a compound which acts as an antioxidant and prevents ubiquitination and degradation of the NF-B inhibitor IB, blocked endothelial cell E-selectin expression in vitro and reduced cell infiltration in LPS-infused rabbits.33 We reported earlier that NF-B inhibition by PDTC ameliorated Ang II–induced cardiac hypertrophy and renal and vascular damage.4 In fact, PDTC probably not only blocks NF-B activation, because it also inhibits the ubiquitin ligase ß-TrCP, which is involved in other signaling pathways.34 Therefore, antioxidative, NF-B, or other signaling pathways might have accounted for the effect in vivo. New strategies with cell-type specific NF-B inhibition as described in this and other recent articles can circumvent this problem. Freund et al14 were the first to show that in mice with cardiomyocyte-specific NF-B suppression, cardiac hypertrophy was significantly reduced after Ang II treatment. Herrmann et al15 used a mouse stroke model and showed that suppressed IB kinase (IKK)-2 activity in neurons markedly reduced cerebral infarct size. The animal models described above consider NF-B as a detrimental factor in the pathogenesis of cardiovascular disease.
NF-B also regulates cell survival and plays a fundamental role in normal cell physiology. Thus, NF-B inhibition may also cause harmful effects. For instance, NF-B inhibition in macrophages increased atherosclerosis in LDL receptor–deficient mice.18 Furthermore, deletion of the IKK-NF-B pathway components results in massive hepatic apoptosis, defects in hematopoiesis, and death in utero.35–37 A transgenic mouse model similar to the Tie-1-N mice was recently established by Kisseleva et al and differed from ours in the overexpression of a mutated IB under the control of the Tie-2 promoter.19 In these mice, endothelial cell NF-B inhibition increased the sensitivity to LPS-induced toxemia and altered vascular integrity. Whether or not the 2 models have an identical transmission of the modified IB in the same cell type is difficult to determine without a direct comparison; such a comparison would be interesting and perhaps revealing. One challenging goal for the future will be the elucidation of protective versus harmful effects of NF-B in cardiovascular disease. These effects seem to be cell- and time-dependent. More detailed studies are needed to investigate this important controversy.
In contrast to atherosclerosis, hypertension-induced vascular injury is not generally considered as an inflammatory and immune disorder.38 We observed increased VCAM-1 and ICAM-1 expression on the endothelium with cell infiltration in hearts and kidneys of hypertensive double-transgenic rats with high Ang II. Direct renin inhibition, Ang II receptor and endothelin receptor blockade, aspirin, or dexamethasone treatment all reduced NF-B activation and ameliorated inflammatory target organ damage in that rat model.17,30,39,40 Our earlier studies and the data presented here support the efficacy of antiinflammatory approaches to cardiovascular diseases. In our Tie-1-N mice, NF-B inhibition in a single cell type, namely endothelial cells, promoted renal protection. As a consequence of suppressed endothelial NF-B activity, reduced VCAM-1 and ICAM-1 expression led to strongly decreased immune cell infiltration in the surrounding tissues. These infiltrating inflammatory cells synthesize and secrete various cytokines that could contribute locally to organ damage.
We focused our attention on the endothelium because this cell layer has been particularly implicated in target-organ damage through endothelial dysfunction mediated by nitric oxide synthase dysfunction, Ang II, and aldosterone.41 We purposely selected a model that we were sure would cause sufficient target-organ damage in mice.22 Our model with high Ang II and low nitric oxide availability mimics a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis, as reviewed elsewhere.42 Nevertheless, our study should not be generalized to situations in which nitric oxide synthase is still active. A better understanding of the complexity of NF-B in the regulation of beneficial and detrimental effects is needed. Therefore, uniquely targeted models such as the one reported here can be extended to other cell types. The approach could give new insights into both pathogenesis and novel therapeutic options.
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Acknowledgments |
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We thank Petra Berkefeld, Jana Czychi, Karin Ganzel, Juliette Bergemann, May-Britt Köhler, Gabriele N’diaye, Mathilde Schmidt, and Sarah Ugowski for their excellent technical assistance.
Sources of Funding
The studies were supported by a grant-in-aid from the European Union (EuReGene). The Deutsche Forschungsgemeinschaft (DFG) supported D.N.M. and F.C.L, and D.N.M. is a Helmholtz fellow.
Disclosures
None.
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Footnotes |
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Original received February 12, 2007; revision received June 3, 2007; accepted June 7, 2007.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. Nadar SK, Tayebjee MH, Messerli F, Lip GY. Target organ damage in hypertension: pathophysiology and implications for drug therapy. Curr Pharm Des. 2006; 12: 1581–1592.[CrossRef][Medline] [Order article via Infotrieve]
2. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004; 15: 1983–1992.
3. Li JJ, Fang CH, Hui RT. Is hypertension an inflammatory disease? Med Hypotheses. 2005; 64: 236–240.[CrossRef][Medline] [Order article via Infotrieve]
4. Muller DN, Dechend R, Mervaala EM, Park JK, Schmidt F, Fiebeler A, Theuer J, Breu V, Ganten D, Haller H, Luft FC. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension. 2000; 35: 193–201.
5. Ruiz-Ortega M, Esteban V, Ruperez M, Sanchez-Lopez E, Rodriguez-Vita J, Carvajal G, Egido J. Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens. 2006; 15: 159–166.[Medline] [Order article via Infotrieve]
6. Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 2000; 20: 645–651.
7. Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J. Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ Res. 2000; 86: 1266–1272.
8. Zhang L, Cheng J, Ma Y, Thomas W, Zhang J, Du J. Dual pathways for nuclear factor kappaB activation by angiotensin II in vascular smooth muscle: phosphorylation of p65 by IkappaB kinase and ribosomal kinase. Circ Res. 2005; 97: 975–982.
9. Collins T, Cybulsky MI. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest. 2001; 107: 255–264.[Medline] [Order article via Infotrieve]
10. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004; 18: 2195–2224.
11. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005; 5: 749–759.[CrossRef][Medline] [Order article via Infotrieve]
12. Brand K, Page S, Walli AK, Neumeier D, Baeuerle PA. Role of nuclear factor-kappa B in atherogenesis. Exp Physiol. 1997; 82: 297–304.[Abstract]
13. de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol. 2005; 25: 904–914.
14. Freund C, Schmidt-Ullrich R, Baurand A, Dunger S, Schneider W, Loser P, El-Jamali A, Dietz R, Scheidereit C, Bergmann MW. Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation. 2005; 111: 2319–2325.
15. Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Kohrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T, Pasparakis M, Schwaninger M. IKK mediates ischemia-induced neuronal death. Nat Med. 2005; 11: 1322–1329.[CrossRef][Medline] [Order article via Infotrieve]
16. Luedde T, Assmus U, Wustefeld T, Meyer zu Vilsendorf A, Roskams T, Schmidt-Supprian M, Rajewsky K, Brenner DA, Manns MP, Pasparakis M, Trautwein C. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest. 2005; 115: 849–859.[CrossRef][Medline] [Order article via Infotrieve]
17. Muller DN, Heissmeyer V, Dechend R, Hampich F, Park JK, Fiebeler A, Shagdarsuren E, Theuer J, Elger M, Pilz B, Breu V, Schroer K, Ganten D, Dietz R, Haller H, Scheidereit C, Luft FC. Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. FASEB J. 2001; 15: 1822–1824.
18. Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Forster I, Kockx MM, Rajewsky K, Kraal G, Hofker MH, de Winther MP. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 112: 1176–1185.[CrossRef][Medline] [Order article via Infotrieve]
19. Kisseleva T, Song L, Vorontchikhina M, Feirt N, Kitajewski J, Schindler C. NF-kappaB regulation of endothelial cell function during LPS-induced toxemia and cancer. J Clin Invest. 2006; 116: 2955–2963.[CrossRef][Medline] [Order article via Infotrieve]
20. Schmidt-Ullrich R, Aebischer T, Hulsken J, Birchmeier W, Klemm U, Scheidereit C. Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development. 2001; 128: 3843–3853.
21. Gustafsson E, Brakebusch C, Hietanen K, Fassler R. Tie-1-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. J Cell Sci. 2001; 114: 671–676.[Abstract]
22. Oestreicher EM, Martinez-Vasquez D, Stone JR, Jonasson L, Roubsanthisuk W, Mukasa K, Adler GK. Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury. Circulation. 2003; 108: 2517–2523.
23. Gross V, Obst M, Kiss E, Janke J, Mazak I, Shagdarsuren E, Muller DN, Langenickel TH, Grone HJ, Luft FC. Cardiac hypertrophy and fibrosis in chronic L-NAME-treated AT2 receptor-deficient mice. J Hypertens. 2004; 22: 997–1005.[CrossRef][Medline] [Order article via Infotrieve]
24. Schmidt-Ullrich R, Tobin DJ, Lenhard D, Schneider P, Paus R, Scheidereit C. NF-kappaB transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth. Development. 2006; 133: 1045–1057.
25. Lim YC, Garcia-Cardena G, Allport JR, Zervoglos M, Connolly AJ, Gimbrone MA Jr, Luscinskas FW. Heterogeneity of endothelial cells from different organ sites in T-cell subset recruitment. Am J Pathol. 2003; 162: 1591–1601.
26. Rikitake Y, Liao JK. Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells. Circulation. 2005; 111: 3261–3268.
27. Krappmann D, Wulczyn FG, Scheidereit C. Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. Embo J. 1996; 15: 6716–6726.[Medline] [Order article via Infotrieve]
28. Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al-Saadi N, Dechend R, Wellner M, Meiners S, Maser-Gluth C, Jeng AY, Webb RL, Luft FC, Muller DN. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation. 2005; 111: 3087–3094.
29. Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fassler R, Betsholtz C. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development. 2004; 131: 1847–1857.
30. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol. 2002; 161: 1679–1693.
31. Morishita R, Sugimoto T, Aoki M, Kida I, Tomita N, Moriguchi A, Maeda K, Sawa Y, Kaneda Y, Higaki J, Ogihara T. In vivo transfection of cis element "decoy" against nuclear factor- kappaB binding site prevents myocardial infarction. Nat Med. 1997; 3: 894–899.[CrossRef][Medline] [Order article via Infotrieve]
32. Vos IH, Govers R, Grone HJ, Kleij L, Schurink M, De Weger RA, Goldschmeding R, Rabelink TJ. NFkappaB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts. Faseb J. 2000; 14: 815–822.
33. Boyle EM Jr, Kovacich JC, Canty TG Jr, Morgan EN, Chi E, Verrier ED, Pohlman TH. Inhibition of nuclear factor-kappa B nuclear localization reduces human E-selectin expression and the systemic inflammatory response. Circulation. 1998; 98 (Suppl): II282–II288.[Medline] [Order article via Infotrieve]
34. Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M, Tanaka H, Yasuda H, Karin M, Kikugawa K. Evidence that reactive oxygen species do not mediate NF-kappaB activation. Embo J. 2003; 22: 3356–3366.[CrossRef][Medline] [Order article via Infotrieve]
35. Gerondakis S, Grossmann M, Nakamura Y, Pohl T, Grumont R. Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. Oncogene. 1999; 18: 6888–6895.[CrossRef][Medline] [Order article via Infotrieve]
36. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-B activity. Annu Rev Immunol. 2000; 18: 621–663.[CrossRef][Medline]
[Order article via Infotrieve]
37. Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, Feng L, Johnson RS, Karin M. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell. 2000; 5: 969–979.[CrossRef][Medline] [Order article via Infotrieve]
38. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
39. Mervaala EM, Muller DN, Park JK, Schmidt F, Lohn M, Breu V, Dragun D, Ganten D, Haller H, Luft FC. Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. Hypertension. 1999; 33: 389–395.
40. Muller DN, Mervaala EM, Schmidt F, Park JK, Dechend R, Genersch E, Breu V, Loffler BM, Ganten D, Schneider W, Haller H, Luft FC. Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000; 36: 282–290.
41. Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res. 2004; 61: 663–670.
42. Schulman IH, Zhou MS, Raij L. Interaction between nitric oxide and angiotensin II in the endothelium: role in atherosclerosis and hypertension. J Hypertens. 2006; Suppl 24: S45–S50.
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