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1
Vodovotz, Y., C. Bogdan, J. Paik, Q. W. Xie i C. Nathan. "Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta." Journal of Experimental Medicine 178, nr 2 (1.08.1993): 605–13. http://dx.doi.org/10.1084/jem.178.2.605.
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Activated mouse peritoneal macrophages produce nitric oxide (NO) via a nitric oxide synthase that is inducible by interferon gamma (IFN-gamma): iNOS. We have studied the mechanisms by which transforming growth factor beta 1 (TGF-beta) suppresses IFN-gamma-stimulated NO production. TGF-beta treatment reduced iNOS specific activity and iNOS protein in both cytosolic and particulate fractions as assessed by Western blot with monospecific anti-iNOS immunoglobulin G. TGF-beta reduced iNOS mRNA without affecting the transcription of iNOS by decreasing iNOS mRNA stability. Even after iNOS was already expressed, TGF-beta reduced the amount of iNOS protein. This was due to reduction of iNOS mRNA translation and increased degradation of iNOS protein. The potency of TGF-beta as a deactivator of NO production (50% inhibitory concentration, 5.6 +/- 2 pM) may reflect its ability to suppress iNOS expression by three distinct mechanisms: decreased stability and translation of iNOS mRNA, and increased degradation of iNOS protein. This is the first evidence that iNOS is subject to other than transcriptional regulation.
2
Gunnett, Carol A., Donald D. Heistad, Angela Loihl i Frank M. Faraci. "Tumor necrosis factor-α impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 279, nr 5 (1.11.2000): R1558—R1564. http://dx.doi.org/10.1152/ajpregu.2000.279.5.r1558.
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We used mice deficient in expression of inducible NO synthase (iNOS −/−) to directly examine the role of iNOS in impaired vasoconstrictor responses following tumor necrosis factor-α (TNF-α). In iNOS +/+ mice, contraction of carotid arteries in response to prostaglandin F2α(PGF2α) was impaired following TNF-α (100 μg/kg ip)( n = 10, P < 0.01). In contrast to responses in wild-type mice, contraction to low concentrations of PGF2αwere normal, but maximum contraction to PGF2αwas impaired in arteries from iNOS −/− mice treated with TNF-α [0.35 ± .0.02 g ( n = 8) following vehicle and 0.25 ± 0.02 g ( n = 7) following TNF-α ( P < 0.05)]. Aminoguanidine, a relatively selective inhibitor of iNOS, partially restored contraction to PGF2αin vessels from iNOS +/+ mice but had no effect in iNOS −/− mice injected with TNF-α, suggesting that a mechanism(s) other than iNOS contributes to impaired responses. In contrast to contractile responses, relaxation of the carotid artery in response to acetylcholine and nitroprusside was not altered following TNF-α in iNOS +/+ or iNOS −/−mice. Responses of carotid arteries from iNOS −/− mice and effects of aminoguanidine suggest that both iNOS-dependent and iNOS-independent mechanisms contribute to impaired contractile responses following TNF-α.
3
Cutler, David. "Unhelpful iNOS". Trends in Pharmacological Sciences 22, nr 12 (grudzień 2001): 609. http://dx.doi.org/10.1016/s0165-6147(00)01963-5.
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Farley, K. S., L. F. Wang, H. M. Razavi, C. Law, M. Rohan, D. G. McCormack i S. Mehta. "Effects of macrophage inducible nitric oxide synthase in murine septic lung injury". American Journal of Physiology-Lung Cellular and Molecular Physiology 290, nr 6 (czerwiec 2006): L1164—L1172. http://dx.doi.org/10.1152/ajplung.00248.2005.
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Inducible nitric oxide synthase (iNOS) contributes importantly to septic pulmonary protein leak in mice with septic acute lung injury (ALI). However, the role of alveolar macrophage (AM) iNOS in septic ALI is not known. Thus we assessed the specific effects of AM iNOS in murine septic ALI through selective AM depletion (via intratracheal instillation of clodronate liposomes) and subsequent AM reconstitution (via intratracheal instillation of donor iNOS+/+ or iNOS−/− AM). Sepsis was induced by cecal ligation and perforation, and ALI was assessed at 4 h: protein leak by the Evans blue (EB) dye method, neutrophil infiltration via myeloperoxidase (MPO) activity, and pulmonary iNOS mRNA expression via RT-PCR. In iNOS+/+ mice, AM depletion attenuated the sepsis-induced increases in pulmonary microvascular protein leak (0.3 ± 0.1 vs. 1.4 ± 0.1 μg EB·g lung−1·min−1; P < 0.05) and MPO activity (37 ± 4 vs. 67 ± 8 U/g lung; P < 0.05) compared with that shown in non-AM-depleted mice. In AM-depleted iNOS+/+ mice, septic pulmonary protein leak was restored by AM reconstitution with iNOS+/+ AM (0.9 ± 0.3 μg EB·g lung−1·min−1) but not with iNOS−/− donor AM. In iNOS−/− mice, sepsis did not induce pulmonary protein leak or iNOS mRNA expression, despite increased pulmonary MPO activity. However, AM depletion in iNOS−/− mice and subsequent reconstitution with iNOS+/+ donor AM resulted in significant sepsis-induced pulmonary protein leak and iNOS expression. Septic pulmonary MPO levels were similar in all AM-reconstituted groups. Thus septic pulmonary protein leak is absolutely dependent on the presence of functional AM and specifically on iNOS in AM. AM iNOS-dependent pulmonary protein leak was not mediated through changes in pulmonary neutrophil influx.
5
Hardiman, Karin M., J. Russell Lindsey i Sadis Matalon. "Lack of amiloride-sensitive transport across alveolar and respiratory epithelium of iNOS(−/−) mice in vivo". American Journal of Physiology-Lung Cellular and Molecular Physiology 281, nr 3 (1.09.2001): L722—L731. http://dx.doi.org/10.1152/ajplung.2001.281.3.l722.
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The extent to which endogenously generated nitric oxide alters Na+transport across the mammalian alveolar epithelium in vivo has not been documented. Herein we measured alveolar fluid clearance and nasal potential differences in mice lacking the inducible form of nitric oxide synthase [iNOS; iNOS(−/−)] and their corresponding wild-type controls [iNOS(+/+)]. Alveolar fluid clearance values in iNOS(+/+) and iNOS(−/−) anesthetized mice with normal oxygenation and acid-base balance were ∼30% of instilled fluid/30 min. In both groups of mice, fluid absorption was dependent on vectorial Na+movement. Amiloride (1.5 mM) decreased alveolar fluid clearance in iNOS(+/+) mice by 61%, whereas forskolin (50 μM) increased alveolar fluid clearance by 55% by stimulating amiloride-insensitive pathways. Neither agent altered alveolar fluid clearance in iNOS(−/−) mice. Hyperoxia upregulated iNOS expression in iNOS(+/+) mice and decreased their amiloride-sensitive component of alveolar fluid clearance but had no effect on the corresponding values in iNOS(−/−) mice. Nasal potential difference measurements were consistent with alveolar fluid clearance in that both groups of mice had similar baseline values, which were amiloride sensitive in the iNOS(+/+) but not in the iNOS(−/−) mice. These data suggest that nitric oxide produced by iNOS under basal conditions plays an important role in regulating amiloride-sensitive Na+channels in alveolar and airway epithelia.
6
Si, Chuanping, Ruihua Zhang, Yuan Hu, Hui Zhang i Huabao Xiong. "Distinct roles of dendritic cell-derived iNOS in the control of effective and regulative dendritic cell differentiation." Journal of Immunology 196, nr 1_Supplement (1.05.2016): 59.2. http://dx.doi.org/10.4049/jimmunol.196.supp.59.2.
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Abstract The immune system exists in a delicate equilibrium between response and tolerance. Dendritic cells (DC) are a plastic lineage able to process and integrate signals from the microenvironment. But the regulation how DCs differentiate to effective or regulatory DC cells are incompletely understood. Inducible nitric oxide synthase (iNOS) derived NO plays critical roles in immune suppression of immune cells. But, it is still not clear what the function of DC cells-derived iNOS is in the regulation in inflammatory diseases. In this study, we demonstrated that DC-derived iNOS regulates balance of effective and regulatory DC cell differentiation. iNOS deficient mice displayed an increased effective DC phenotypes, whereas the percentage of regulatory DCs were comparable in wild-type and iNOS deficient mice in vivo and in vitro. The results were further supported by increased effective DCs from iNOS−/− BMDC cells. Activation of DCs by LPS/IFNg resulted in the expression of iNOS in WT mice. The iNOS inhibitor L-NIL enhanced effective DCs differentiation, mimicking the effect observed in iNOS deficient mice. NO donor SNAP suppressed effective DCs. iNOS−/− DCs result in more enhanced T cell activation. iNOS−/− mice infected with Citrobacter Rodentium led to more severe intestinal inflammation compared to WT mice and the results were correlated with more inflammatory cells infiltration in iNOS−/− in colon tissues. And iNOS−/− mice showed increased effective DCs in colon tissues than that in WT mice. Our results suggest that DC-derived iNOS negatively controls effective DC development and targeting DC-derived iNOS would lead to the new therapies for autoimmune/inflammatory diseases.
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Melillo, G., T. Musso, A. Sica, L. S. Taylor, G. W. Cox i L. Varesio. "A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter." Journal of Experimental Medicine 182, nr 6 (1.12.1995): 1683–93. http://dx.doi.org/10.1084/jem.182.6.1683.
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Picolinic acid, a catabolite of L-tryptophan, activates the transcription of the inducible nitric oxide synthase gene (iNOS) in IFN-gamma-treated murine macrophages. We performed functional studies on the 5' flanking region of the iNOS gene linked to a CAT reporter gene to identify the cis-acting element(s) responsible for the activation of iNOS transcription by picolinic acid. Transient transfection assays showed that the full-length iNOS promoter in the murine macrophage cell line ANA-1 was activated by the synergistic interaction between IFN-gamma and picolinic acid. Deletion or mutation of the iNOS promoter region from -227 to -209, containing a sequence homology to a hypoxia-responsive enhancer (iNOS-HRE), decreased picolinic acid- but not LPS-induced CAT activity by more than 70%. Functional studies using a tk promoter-CAT reporter gene plasmid demonstrated that the iNOS-HRE was sufficient to confer inducibility by picolinic acid but not by IFN-gamma or LPS. Electrophoretic mobility shift assays confirmed that picolinic acid alone induced a specific binding activity to the iNOS-HRE. Furthermore, we found that the iNOS-HRE activity was inducible by hypoxia and that hypoxia in combination with IFN-gamma activated the iNOS promoter in transient transfection assays and induced iNOS transcription and mRNA expression. These data establish that the iNOS-HRE is a novel regulatory element of the iNOS promoter activity in murine macrophages and provide the first evidence that iNOS is a hypoxia-inducible gene.
8
Chu, Wei, Lirong Cao, Gui Daokun i Jiali Zhao. "iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway". Journal of Immunology Research 2021 (16.08.2021): 1–10. http://dx.doi.org/10.1155/2021/4549221.
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Inducible nitric oxide synthase (iNOS), accompanied with protumor and antitumor activity, has been studied in multiple cancers. However, the role of iNOS expression in osteosarcoma (OS) is far from being fully understood. In present work, iNOS levels were detected in OS tissues and cell lines. Colony formation assay, Transwell assay, and fow cytometer were used to assess proliferation, migration, invasion, and apoptosis abilities in vitro after iNOS inhibition. Western blotting determined the expressions of iNOS, MMP2, MMP9, C-MYC, Ki67, PCNA, and β-catenin. Mice transfected with OS cells were to evaluate tumor formation. IHC assay was to evaluate the expressions of iNOS and β-catenin in mice. The results showed that iNOS was upregulated in both OS tissues and cells compared with that in matched normal tissues or cells. And we found that proliferation, migration, and invasion numbers of OS cells were decreased, and apoptosis numbers of OS cells were increased after iNOS inhibition. MMP2, MMP9, C-MYC, Ki67, and PCNA levels were also reduced in OS cells treated with iNOS inhibition. Else, iNOS inhibition would suppress β-catenin expression in OS cells to regulate MMP2, MMP9, C-MYC, Ki67, and PCNA expressions. In addition, tumor formation, iNOS expression, and β-catenin expression were inhibited in mice transplanted with iNOS knockout OS cells. These results indicated that iNOS might be a potential therapeutic target for OS.
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Miller, Barbara H., Rutilio A. Fratti, Jens F. Poschet, Graham S. Timmins, Sharon S. Master, Marcos Burgos, Michael A. Marletta i Vojo Deretic. "Mycobacteria Inhibit Nitric Oxide Synthase Recruitment to Phagosomes during Macrophage Infection". Infection and Immunity 72, nr 5 (maj 2004): 2872–78. http://dx.doi.org/10.1128/iai.72.5.2872-2878.2004.
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ABSTRACT Inducible nitric oxide synthase (iNOS) is a cytoplasmic protein responsible for the generation of nitric oxide (NO · ) in macrophages. In this work, we hypothesized that the intracellular localization of iNOS is significant for effective delivery of NO · to phagosomes containing ingested microorganisms. Using immunofluorescence microscopy and Western blot analysis, iNOS was shown to localize in the vicinity of phagosomes containing latex beads in stimulated macrophages. iNOS also localized to phagosomes containing Escherichia coli. The colocalization of iNOS with ingested latex beads was an actin-dependent process, since treatment with the actin microfilament disrupter cytochalasin D prevented iNOS recruitment to latex bead phagosomes. In contrast to E. coli and inert particle phagosomes, mycobacterial phagosomes did not colocalize with iNOS. This study demonstrates that (i) iNOS can be recruited to phagosomes; (ii) this recruitment is dependent on a functional actin cytoskeleton; (iii) certain microorganisms have the ability to prevent or reduce colocalization with iNOS; and (iv) spatial exclusion of iNOS may play a role in Mycobacterium tuberculosis pathogenesis.
10
Chicoine, Louis G., Edith Tzeng, Rebekah Bryan, Steven Saenz, Michael L. Paffett, Joelle Jones, C. Richard Lyons, Thomas C. Resta, Leif D. Nelin i Benjimen R. Walker. "Intratracheal adenoviral-mediated delivery of iNOS decreases pulmonary vasoconstrictor responses in rats". Journal of Applied Physiology 97, nr 5 (listopad 2004): 1814–22. http://dx.doi.org/10.1152/japplphysiol.00193.2004.
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We hypothesized that adenovirus-mediated inducible nitric oxide synthase (iNOS) gene transduction of the lung would result in time-dependent iNOS overexpression and attenuate the vascular constrictor responses to a thromboxane mimetic, U-46619. Rats were treated via the trachea with surfactant alone (sham), surfactant containing an adenoviral construct with a cytomegalovirus promoter-regulated human iNOS gene (Adeno-iNOS), or an adenoviral construct without a gene insert (Adeno-Control). Adeno-iNOS-transduced rats demonstrated human iNOS mRNA and increased iNOS protein levels only in the lungs. Immunohistochemistry of lungs from Adeno-iNOS-treated animals demonstrated transgene expression in alveolar wall cells. In the lungs from Adeno-iNOS-transduced rats, the expression of iNOS protein and exhaled nitric oxide concentrations were increased on days 1–4 and 7 but returned to baseline values by day 14. The administration of the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine dihydrochloride (l-NIL) decreased exhaled nitric oxide concentrations to levels found in Adeno-Control-transduced lungs. In a second group of rats, the segmental vasoconstrictor responses to U-46619 were determined in isolated, perfused lungs 3 days after transduction. Lungs from rats transduced with Adeno-iNOS had reduced total, arterial, and venous vasoconstrictor responses to U-46619 compared with sham, Adeno-Control, and control groups. In a third set of experiments, the response to 400 nM U-46619 in the presence of 10 μM l-NIL was not different in the isolated lungs from Adeno-Control- and Adeno-iNOS-transduced rats. We conclude that adenovirus-mediated iNOS gene transduction of the lung results in time-dependent iNOS overexpression, which attenuates the vascular constrictor responses to the thromboxane mimetic U-46619.
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Hickman-Davis, Judy M., J. Russell Lindsey i Sadis Matalon. "Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis". Infection and Immunity 69, nr 10 (1.10.2001): 6401–10. http://dx.doi.org/10.1128/iai.69.10.6401-6410.2001.
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ABSTRACT We previously reported that congenic C57BL/6 inducible nitric oxide synthase−/− (iNOS−/−) mice infected withMycoplasma pulmonis developed higher bacterial numbers and lung lesion scores than C57BL/6 iNOS+/+ controls but had similar lung nitrotyrosine levels. The present studies investigated the role of inflammatory cells in nitrotyrosine formation during mycoplasmal infection. iNOS+/+ and iNOS−/−mice were injected with cyclophosphamide (CYP) and inoculated with 107 CFU of M. pulmonis. CYP pretreatment ofM. pulmonis-infected iNOS+/+ and iNOS−/− mice reduced polymorphonuclear cells (PMNs) within bronchoalveolar lavages (BALs) by 88 and 72%, respectively, and whole-lung myeloperoxidase levels by 80 and 78%, respectively, at 72 h postinfection but did not alter the number of alveolar macrophages (AMs) in BALs. CYP treatment also significantly decreased nitrate and nitrite (NOx) levels in BALs and plasma of infected iNOS+/+ mice, whereas neither CYP nor mycoplasmal infection altered NOx in iNOS−/− mice. CYP reduced lung nitrotyrosine levels in both iNOS+/+ and iNOS−/− mice to uninfected-control levels as shown by immunohistochemical staining and enzyme-linked immunosorbent assay and inhibited mycoplasmal killing by iNOS+/+ mice in vivo. CYP inhibited the production of gamma interferon-inducible NOx by iNOS+/+ AMs in vitro but did not alter the number of iNOS-positive AMs, as detected by immunocytochemistry. In addition, AMs from CYP-treated iNOS+/+ mice had significantly decreased ability to kill mycoplasmas in vitro. These results demonstrate that reactive species generated by inflammatory cells as well as PMN myeloperoxidase are important contributors to nitrotyrosine formation during mycoplasmal infection and that treatment with CYP decreases NO⋅ production by AMs and inhibits mycoplasmal killing.
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McCafferty, Donna-Marie, Elaine Sihota, Marcelo Muscara, John L. Wallace, Keith A. Sharkey i Paul Kubes. "Spontaneously developing chronic colitis in IL-10/iNOS double-deficient mice". American Journal of Physiology-Gastrointestinal and Liver Physiology 279, nr 1 (1.07.2000): G90—G99. http://dx.doi.org/10.1152/ajpgi.2000.279.1.g90.
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Mice deficient in both inducible nitric oxide synthase (iNOS) and interleukin (IL)-10 (iNOS−/−/IL-10−/−) were created to examine the role of iNOS in spontaneously developing intestinal inflammation. IL-10−/−/iNOS−/−mice were compared with IL-10−/−(iNOS+/+) littermates over 6 mo. RT-PCR, Western blot analysis, and immunohistochemistry were performed to measure iNOS message and protein levels. Plasma nitrate/nitrite (NOx) levels were assessed by HPLC. Damage scores (macroscopic and microscopic) and granulocyte infiltration were assessed. At 3–4 wk, IL-10−/−and IL-10−/−/iNOS−/−mice had no signs of colonic inflammation or granulocyte infiltration. Plasma NOxlevels were not different from controls. By 3–4 mo, IL-10−/−mice had increased damage scores and granulocyte infiltration concurrent with increased mRNA and protein synthesis (restricted to the epithelium) for iNOS in intestinal tissues but not other tissues. Plasma NOxlevels increased fivefold. Interestingly, in the absence of iNOS induction or increased plasma NOx, iNOS−/−/IL-10−/−mice had damage and granulocyte infiltration equivalent to those observed in IL-10−/−littermates. These data suggest that iNOS does not impact on the development or severity of spontaneous chronic inflammation in IL-10-deficient mice.
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Pérez-Sala, Dolores, Eva Cernuda-Morollón, Manuela Díaz-Cazorla, Fernando Rodríguez-Pascual i Santiago Lamas. "Posttranscriptional regulation of human iNOS by the NO/cGMP pathway". American Journal of Physiology-Renal Physiology 280, nr 3 (1.03.2001): F466—F473. http://dx.doi.org/10.1152/ajprenal.2001.280.3.f466.
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Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1β plus tumor necrosis factor (TNF)-α reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1β/TNF-α-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
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Qi, Wen-Ning, Long-En Chen, Li Zhang, Jerry P. Eu, Anthony V. Seaber i James R. Urbaniak. "Reperfusion injury in skeletal muscle is reduced in inducible nitric oxide synthase knockout mice". Journal of Applied Physiology 97, nr 4 (październik 2004): 1323–28. http://dx.doi.org/10.1152/japplphysiol.00380.2004.
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Inducible nitric oxide synthase (iNOS) participates in many pathological events, and selective inhibition of iNOS has been shown to reduce ischemia-reperfusion (I/R) injury in different tissues. To further confirm its role in this injury process, I/R injury was observed in denervated cremaster muscles of iNOS-deficient (iNOS−/−) and wild-type mice. After 3-h ischemia and 90-min reperfusion, blood flow in reperfused muscle was 80 ± 8.5% (mean ± SE) of baseline at 10-min reperfusion and completely returned to the preischemia baseline after 20 min in iNOS−/− mice. In contrast, blood flow was 32 ± 7.4% at 10 min and increased to 60 ± 20% of the baseline level at 90 min in wild-type mice ( P < 0.001 vs. iNOS−/− mice at all time points). The increased muscle blood flow in iNOS−/− mice was associated with significantly less vasospasm in all three sizes of arterial vessel size categories. The weight ratio to the contralateral muscle not subjected to I/R was greater in wild-type mice (173 ± 11%) than in iNOS−/− mice (117 ± 3%; P < 0.01). Inflammation and neutrophil extravasation were also more severe in wild-type mice. Western blot analysis demonstrated an absence of iNOS protein band in iNOS−/− mice and upregulation of iNOS protein expression in wild-type mice. Our results confirm the importance of iNOS in I/R injury. Upregulated iNOS exacerbates I/R injury and appears to be a therapeutic target in protection of tissues against this type of injury.
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Simon, Priscilla, Sarah Sharman, Chunwan Lu, Dafeng Yang, Amy Paschall i Kebin Liu. "The NF-κB p65 and p50 homodimer cooperate with pSTAT1 to synergistically activate iNOS transcription in cancer cells and myeloid cells (INM1P.440)". Journal of Immunology 194, nr 1_Supplement (1.05.2015): 56.17. http://dx.doi.org/10.4049/jimmunol.194.supp.56.17.
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Abstract Inducible nitric oxide synthase (iNOS) metabolizes L-arginine to produce NO, which was originally identified in myeloid cells as a host defense mechanism against pathogens. However, recent studies have revealed that iNOS is often induced in both tumor and myeloid cells in the tumor microenvironment. Compelling experimental data have shown that iNOS can promote or suppress tumor development in certain cellular conditions. The molecular mechanisms underlying this contrasting function of iNOS is unknown. Because iNOS is often induced by inflammatory signals, it is likely that the opposite functions of iNOS might be controlled by inflammatory signaling pathways. We show here that proinflammatory IFN-γ and NF-κB signals synergistically induce iNOS expression in human colon cancer cells. We further demonstrated that NF-κB directly binds to the NOS2 promoter to regulate iNOS expression. Although the IFN-γ and NF-κB signaling pathways alone are insufficient to induce iNOS expression in myeloid cells, IFN-γ and NF-κB can synergistically induce iNOS expression. We determined that IFN-γ up-regulates IRF8 expression to augment NF-κB induction of iNOS expression. We observed that the p65/p65 and p50/p50 homodimers, not the common canonical p65/p50 heterodimer, directly binds to the nos2 promoter to regulate iNOS expression in myeloid cells. Our results thus determine that the IFN-γ-induced IRF8 acts in concert with the NF-κB p65/p65 and p50/p50 homodimers to regulate iNOS expression.
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Nathan, Carl, Noel Calingasan, Jon Nezezon, Aihao Ding, M. Scott Lucia, Krista La Perle, Michele Fuortes i in. "Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase". Journal of Experimental Medicine 202, nr 9 (31.10.2005): 1163–69. http://dx.doi.org/10.1084/jem.20051529.
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Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human β-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS+/+ or iNOS−/−, and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased β-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of β-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.
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Marjanovic, Jasna A., Aleksandra Stojanovic, Viktor Brovkovych, Randal A. Skidgel i Xiaoping Du. "Inducible Nitric Oxide Synthase Plays a Stimulatory Role in Platelet Activation." Blood 106, nr 11 (16.11.2005): 1650. http://dx.doi.org/10.1182/blood.v106.11.1650.1650.
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Abstract Platelets generate nitric oxide (NO) in response to agonist stimulation. Previous reports have shown that the endothelial nitric oxide synthase (eNOS) plays a role in agonist-stimulated platelet NO production and in platelet activation. Here we show that platelets from eNOS knockout mice (eNOS−/−) showed only partial reduction in thrombin-induced NO production compared to wild type platelets (50% reduction), indicating the presence of another NOS isoform in platelets. More importantly, we show that resting platelets express functional inducible nitric oxide synthase (iNOS), which participates in platelet activation. Compared to wild type platelets, thrombin-induced NO production was reduced by 54% in platelets isolated from iNOS knockout mice (iNOS−/−), indicating an iNOS-dependent NO production in platelets induced by thrombin. Since thrombin-induced NO production occurs during the first 3 min of thrombin stimulation, our findings provide the first evidence for a short-term regulation of iNOS activity independent of transcription regulation. In contrast, previous description of iNOS activation was primarily at the transcriptional level and required much longer time of induction. To determine the role of iNOS in platelet activation, platelets from wild type and iNOS−/− mice were stimulated with low concentrations of agonists. iNOS−/− platelets exhibited lower aggregation and secretion response compared to wild type control, indicating that iNOS plays a stimulatory role in platelet activation. We also examined the effect of iNOS inhibitors on platelet activation. Human and mouse platelets preincubated with iNOS specific inhibitors, 1400W and aminoguanidine, exhibited a dose-dependent inhibition of platelet secretion and aggregation induced by either low-dose thrombin or collagen. Furthermore, the inhibitory effect of iNOS-specific inhibitors was only shown in wild type mouse platelets, but was lacking in iNOS−/− platelets. Thus, activation of both iNOS and eNOS is important in agonist-induced NO production which stimulates platelet secretion and aggregation.
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Upmacis, Rita K., Hao Shen, Lea Esther S. Benguigui, Brian D. Lamon, Ruba S. Deeb, Katherine A. Hajjar i David P. Hajjar. "Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice". American Journal of Physiology-Heart and Circulatory Physiology 301, nr 2 (sierpień 2011): H617—H624. http://dx.doi.org/10.1152/ajpheart.00667.2010.
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Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease-promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild-type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A2 (TxA2) or antithrombotic prostacyclin (PGI2). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice.
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Virág, László, György Haskó, Andrew L. Salzman i Csaba Szabó. "NADPH Diaphorase Histochemistry Detects Inducible Nitric Oxide Synthetase Activity in the Thymus of Naive and Staphylococcal Enterotoxin B-stimulated Mice". Journal of Histochemistry & Cytochemistry 46, nr 7 (lipiec 1998): 787–91. http://dx.doi.org/10.1177/002215549804600701.
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Here we examined the changes in NADPH diaphorase (NADPHd) and inducible nitric oxide synthetase (iNOS) positivity in the medulla of the mouse thymus in response to treatment with the superantigen, Staphylococcal enterotoxin B (SEB). A few NADPHd+ and iNOS+ cells scattered in the medulla were detected in the thymi of naive mice. SEB induced the appearance of a large number of NADPHd+- and iNOS-immunoreactive cells in the thymic medulla. In the thymus of iNOS-deficient mice, a total absence of these NADPHd+ and iNOS+ medullary cells was found both under basal conditions and after SEB stimulation. With the NADPHd reaction, only endothelial staining was detected in the thymi of iNOS-deficient mice. Our data indicate that NADPHd+ cells in the thymic medulla express iNOS and that SEB induces iNOS expression in the mouse thymus.
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Minhas, Richa, i Yogita Bansal. "iNOS inhibitors: Benzimidazole-coumarin derivatives to combat inflammation". European Journal of Chemistry 13, nr 3 (30.09.2022): 307–18. http://dx.doi.org/10.5155/eurjchem.13.3.307-318.2282.
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Inducible nitric oxide synthase (iNOS) plays an important role in the inflammatory processes via accelerating the production of nitric oxide (NO). The efforts to develop small molecules as selective inhibitors of iNOS are being reported across the globe. The current study explores varied benzimidazole-coumarin derivatives as anti-iNOS agents. Literature survey suggests 2-aminobenzimidazole, coumarin nucleus, and 4-atom linker as important structural components for iNOS inhibition. Target compounds were designed and synthesized by coupling 2-aminobenzimidazole with (un)substituted coumarin through different linkers. These were docked in iNOS (1QW4) and nNOS (1QW6) targets to ascertain their iNOS selectivity, and evaluated for NO and iNOS inhibitory activities in vitro. The most active inhibitors were subsequently evaluated for acute toxicity and anti-inflammatory activity using carrageenan-induced rat paw edema model in vivo. All compounds possessed moderate to good NO and iNOS inhibitory activities. Compounds 14a, 14b, 14d, and 14e were the most potent inhibitors in vitro. These were found to significantly reduce the inflammation. Compounds 14d and 14e have been identified as the most potent iNOS inhibitors to combat inflammation. These derivatives may serve as potential compounds as such against iNOS, or as leads for the development of novel anti-iNOS agents.
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Lu, Min, PingPing Li, Jan Pferdekamper, WuQiang Fan, Maziyar Saberi, Simon Schenk i Jerrold M. Olefsky. "Inducible Nitric Oxide Synthase Deficiency in Myeloid Cells Does Not Prevent Diet-Induced Insulin Resistance". Molecular Endocrinology 24, nr 7 (1.07.2010): 1413–22. http://dx.doi.org/10.1210/me.2009-0462.
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Abstract Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFα treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.
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Kanno, K., Y. Hirata, T. Imai, M. Iwashina i F. Marumo. "Regulation of inducible nitric oxide synthase gene by interleukin-1 beta in rat vascular endothelial cells". American Journal of Physiology-Heart and Circulatory Physiology 267, nr 6 (1.12.1994): H2318—H2324. http://dx.doi.org/10.1152/ajpheart.1994.267.6.h2318.
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To elucidate the regulation of endothelial inducible nitric oxide synthase (iNOS), we studied the effects of interleukin (IL)-1 beta on production of nitric oxide (NO) and expression of iNOS mRNA and iNOS protein in cultured rat aortic endothelial cells (ECs) by measurement of NO2-/NO3- (NOx) and Northern blot and Western blot analyses. Among several cytokines and bacterial lipopolysaccharide tested, IL-1 beta most effectively stimulated NOx production. IL-1 beta dose and time dependently stimulated NOx production. Northern blot analysis using cDNA for mouse liver iNOS as a probe showed that IL-1 beta induced expression of iNOS mRNA and stimulated NOx production in a dose- and time-dependent manner. Transforming growth factor (TGF)-beta and dexamethasone blocked the IL-1 beta-induced NOx production as well as expression of iNOS mRNA and protein. TGF-beta dose dependently inhibited the IL-1 beta-induced NOx production and iNOS mRNA expression. Northern blot analysis for the decay of the IL-1 beta-induced iNOS mRNA revealed the approximate half-life of 4 h. These data indicate that IL-1 beta induces iNOS gene expression and de novo synthesis of iNOS and subsequent NO generation in vascular endothelium and that TGF-beta and glucocorticoid block iNOS gene expression at the transcriptional level.
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Pautz, Andrea, Katrin Linker, Thomas Hubrich, Riku Korhonen, Sebastian Altenhöfer i Hartmut Kleinert. "The Polypyrimidine Tract-binding Protein (PTB) Is Involved in the Post-transcriptional Regulation of Human Inducible Nitric Oxide Synthase Expression". Journal of Biological Chemistry 281, nr 43 (1.09.2006): 32294–302. http://dx.doi.org/10.1074/jbc.m603915200.
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Human inducible nitric oxide synthase (iNOS) expression is regulated by transcriptional and post-transcriptional mechanisms. We have recently shown that the multifunctional RNA-binding proteins KH-type splicing regulatory protein and tristetraprolin are critically involved in the post-transcriptional regulation of human iNOS expression. Several reports have shown that KH-type splicing regulatory protein colocalizes with the polypyrimidine tract-binding protein (PTB), and both RNA-binding proteins seem to interact with the same mRNAs. Therefore we analyzed the involvement of PTB in human iNOS expression. In human DLD-1 cells, cytokine incubation necessary to induce iNOS expression did not change PTB localization or expression. However, intracellular binding of PTB to the human iNOS mRNA increased after cytokine stimulation. Overexpression of PTB resulted in enhanced cytokine-induced iNOS expression. Accordingly, small interfering RNA-mediated knock down of PTB reduced cytokine-dependent iNOS expression. Recombinant PTB displayed binding to an UC-rich sequence in the 3′-untranslated region of the human iNOS mRNA. Transfection experiments showed that PTB mediates its effect on iNOS expression via binding to this region. The underlying mechanism is based on a modulation of iNOS mRNA stability. In summary, human iNOS is the first example of a human pro-inflammatory gene regulated by PTB on the level of mRNA stability.
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Zheng, Xi-Long, Keith A. Sharkey i Morley D. Hollenberg. "Induction of nitric oxide synthase in rat gastric smooth muscle preparations". American Journal of Physiology-Gastrointestinal and Liver Physiology 273, nr 5 (1.11.1997): G1101—G1107. http://dx.doi.org/10.1152/ajpgi.1997.273.5.g1101.
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The induction in vitro of inducible nitric oxide synthase (iNOS) in intact gastric circular (CM) and longitudinal (LM) smooth muscle preparations was evaluated 1) pharmacologically, by the appearance of 1 mM l-arginine (l-Arg)-induced relaxation in a precontracted tissue; 2) biochemically, according to the appearance of iNOS mRNA using a reverse transcriptase-polymerase chain reaction; and 3) immunohistochemically, using an iNOS-specific antibody. Functionally, iNOS induction affected the contractile properties of the CM but not the LM preparation. The time course of iNOS induction monitored pharmacologically paralleled exactly the appearance of iNOS mRNA. The relaxant response to l-Arg in iNOS-induced CM tissues was blocked by the iNOS inhibitor aminoguanidine and by the guanylyl cyclase inhibitor LY-83583. The addition of oxyhemoglobin to the organ bath also attenuated the relaxant response, but tetrodotoxin had no effect. The transcriptional inhibitor actinomycin D completely blocked iNOS induction as assessed by both pharmacological and biochemical criteria. In iNOS-induced preparations the iNOS immunoreactivity was not detected in the smooth muscle elements but was localized in a layer of macrophage-related cells that were in apposition to the CM smooth muscle elements. We conclude that the spontaneous induction of iNOS in rat gastric tissue can affect the pharmacomechanical reactivity of the CM elements and that this regulation of the CM contractility is due to the induction of iNOS in a set of macrophage-related cells that are closely apposed to the CM elements so that they selectively affect only the contractility of the CM preparation.
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Kang, Jung-Hoon, Seo-Yoon Chang, Hyun-Jong Jang, Dong-Bin Kim, Gyeong Ryul Ryu, Seung Hyun Ko, In-Kyung Jeong, Yang-Hyeok Jo i Myung-Jun Kim. "Exendin-4 inhibits interleukin-1β-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F β-cells". Journal of Endocrinology 202, nr 1 (27.04.2009): 65–75. http://dx.doi.org/10.1677/joe-08-0507.
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Cytokines such as interleukin-1β (IL-1β) stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction leading to β-cell damage. Meanwhile, glucagon-like peptide-1 (GLP-1) and its potent analog exendin-4 (EX-4) were well known for β-cell proliferation. However, the protective mechanisms of GLP-1 in β-cells exposed to cytokines were not fully elucidated. Therefore, the effects of EX-4 on the IL-1β-induced iNOS gene expression were investigated employing RINm5F β-cells. EX-4 inhibited IL-1β-induced iNOS protein expression and nitrite production. However, northern blot and promoter analyses showed that EX-4 failed to inhibit IL-1β-induced iNOS mRNA expression and iNOS promoter activity. By electrophoretic mobility shift assay (EMSA), EX-4 did not alter the binding activity of NF-κB to the iNOS promoter. Consistent with the EMSA result, EX-4 did not inhibit nuclear translocation of p65. We also tested the effect of EX-4 on iNOS mRNA stability. Actinomycin D chase experiments showed that EX-4 did not affect the decay rate of iNOS mRNA and the promoter assay using the construct containing 3′-untranslated region of iNOS showed that EX-4 did not alter the stability of iNOS mRNA. Meanwhile, forskolin significantly inhibited IL-1β-induced iNOS protein, which was reversed by H-89, a protein kinase A (PKA) inhibitor. Moreover, EX-4 pretreatment restored IL-1β-induced decrease in cAMP toward control level. Additionally, the cycloheximide chase study demonstrated that EX-4 significantly accelerated iNOS protein degradation. We therefore concluded that EX-4 inhibited IL-1β-induced iNOS protein and nitrite production via cAMP/PKA system irrespective of both transcriptional and posttranscriptional mechanisms of iNOS gene, and this inhibitory effect of EX-4 appears to be regulated at posttranslational level.
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Bayır, Hülya, Valerian E. Kagan, Grigory G. Borisenko, Yulia Y. Tyurina, Keri L. Janesko, Vincent A. Vagni, Timothy R. Billiar, Deborah L. Williams i Patrick M. Kochanek. "Enhanced Oxidative Stress in iNOS-Deficient Mice after Traumatic Brain Injury: Support for a Neuroprotective Role of iNOS". Journal of Cerebral Blood Flow & Metabolism 25, nr 6 (16.02.2005): 673–84. http://dx.doi.org/10.1038/sj.jcbfm.9600068.
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Studies in experimental traumatic brain injury (TBI) suggest both deleterious and protective effects of inducible nitric oxide synthase (iNOS). Early after injury, iNOS may be detrimental via formation of peroxynitrite and iNOS inhibitors are protective. In contrast, we reported impaired long-term functional outcome after TBI in iNOS knockout (ko) versus wild-type (wt) mice. To elucidate potential neuroprotective and neurotoxic mechanisms for iNOS, we studied nitric oxide formation by electron paramagnetic resonance (EPR) spectroscopy using diethyldithiocarbamate—iron (DETC—Fe) as a spin trap and markers of nitrosative ( S-nitrosothiol (RSNO, Fluorescent assay); nitrotyrosine (3NT, ELISA)) and oxidative stress (ascorbate, HPLC) at 72 h after controlled cortical impact (CCI) in iNOS ko and wt and in uninjured iNOS ko and wt mice. 3NT immunostaining with macrophage and myeloperoxidase (MPO) dual labeling was also assessed in brain sections. Brain DETC—Fe—NO low-temperature EPR signal intensity was ∼2-fold greater in wt versus iNOS ko at 72 h after CCI. Ascorbate levels decreased in injured hemisphere in wt and iNOS ko versus uninjured —this decrease was more pronounced in iNOS ko. In wt mice, RSNO and 3NT levels were increased after CCI versus uninjured (50% and 400%, respectively, P<0.05). RSNO levels were not increased in iNOS ko after CCI. Nitrotyrosine levels increased after CCI in wt and ko versus respective uninjured —this increase was more pronounced in wt (2.34±0.95 versus 1.27±0.49 pmol/mg protein, P<0.05). Increased 3NT immunoreactivity was detected in wt versus iNOS ko at 72 h after CCI, and colocalized with macrophage marker and MPO. Our data support a role for iNOS-derived NO as an endogenous antioxidant after CCI. iNOS also contributes protein nitrosylation and nitration. Colocalization of 3NT with macrophages and MPO suggests generation of nitrating agents by macrophages and/or phagocytosis of nitrated proteins.
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Cassini-Vieira, Puebla, Fernanda Assis Araújo, Filipi Leles da Costa Dias, Remo Castro Russo, Silvia Passos Andrade, Mauro Martins Teixeira i Luciola Silva Barcelos. "iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants". Mediators of Inflammation 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/138461.
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There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS−/−) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS−/−mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS−/−mice. In contrast, the iNOS−/−implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS−/−mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice.
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Kolios, G., N. Rooney, C. T. Murphy, D. A. F. Robertson i J. Westwick. "Expression of inducible nitric oxide synthase activity in human colon epithelial cells: modulation by T lymphocyte derived cytokines". Gut 43, nr 1 (1.07.1998): 56–63. http://dx.doi.org/10.1136/gut.43.1.56.
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Background—Nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) expression are increased in colonic biopsy specimens from patients with ulcerative colitis, but the cellular source of NO production is not known.Aims—To examine the distribution of iNOS in human colonic mucosa and to explore the ability of T lymphocyte derived cytokines to regulate iNOS expression and activity in human colonic epithelial cells.Methods—iNOS expression was examined using immunohistochemistry in colonic biopsy samples from 12 patients with ulcerative colitis and three with infectious colitis and compared with 10 normal controls. In vitro iNOS expression and activity were determined in HT-29 cell cultures; nitrite levels were measured using a fluorescent substrate, iNOS mRNA expression by northern blot analysis, and iNOS protein expression by western blot analysis.Results—No iNOS expression was detected (10 of 10) in non-inflamed mucosa derived from normal controls. In 11 of 12 cases of newly diagnosed ulcerative colitis, iNOS protein was expressed in the epithelial cells, while no other positive cells were found in the lamina propria. Similar iNOS labelling was found in colonic biopsy samples from patients with infectious colitis in the acute phase, but when re-examined in samples from patients in total remission, no iNOS staining was observed. Both interleukin (IL)-13 and IL-4, but not IL-10, are potent inhibitors of iNOS expression and activity induced by an optimal combination of cytokines, namely IL-1α, tumour necrosis factor α and interferon γ.Conclusions—The data suggest that the epithelium is the major source of iNOS activity in ulcerative colitis and that IL-13 and IL-4 may act as intrinsic regulators of NO generation in intestinal inflammation.
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Somers, Julie R., Paul L. Beck, James P. Lees-Miller, Daniel Roach, Yan Li, J. Guo, Steven Loken, Shan Zhan, Lisa Semeniuk i Henry J. Duff. "iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin". American Journal of Physiology-Heart and Circulatory Physiology 295, nr 3 (wrzesień 2008): H1122—H1131. http://dx.doi.org/10.1152/ajpheart.00386.2008.
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Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS−/− and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS−/− mice had improved systolic performance ( P < 0.001) and less heart block ( P < 0.0001); larger sodium current density and lower serum TNF-α levels ( P < 0.03); and less apoptosis ( P < 0.01) resulting in improved survival ( P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS−/− mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.
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Jones, Rachel J., David Jourd'heuil, John C. Salerno, Susan M. E. Smith i Harold A. Singer. "iNOS regulation by calcium/calmodulin-dependent protein kinase II in vascular smooth muscle". American Journal of Physiology-Heart and Circulatory Physiology 292, nr 6 (czerwiec 2007): H2634—H2642. http://dx.doi.org/10.1152/ajpheart.01247.2006.
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Nitric oxide synthase (NOS) expression is regulated transcriptionally in response to cytokine induction and posttranslationally by palmitoylation and trafficking into perinuclear aggresome-like structures. We investigated the effects of multifunctional calcium/calmodulin-dependent protein kinase II protein kinase (CaMKII) on inducible NOS (iNOS) trafficking in cultured rat aortic vascular smooth muscle cells (VSMCs). Immunofluorescence and confocal microscopy demonstrated colocalization of iNOS and CaMKIIδ2 with a perinuclear distribution and concentration in aggresome-like structures identified by colocalization with γ-tubulin. Furthermore, CaMKIIδ2 coimmunoprecipitated with iNOS in a CaMKII activity-dependent manner. Addition of Ca2+-mobilizing stimuli expected to activate CaMKII; a purinergic agonist (UTP) or calcium ionophore (ionomycin) caused a general redistribution of iNOS from cytosolic to membrane and nuclear fractions. Similarly, adenoviral expression of a constitutively active CaMKIIδ2 mutant altered iNOS localization, shifting iNOS from the cytosolic fraction. Suppression of CaMKIIδ2 using an adenovirus expressing a short hairpin, small interfering RNA increased nuclear iNOS localization in resting cells but inhibited ionomycin-induced translocation of iNOS to the nucleus. Following addition of these chronic and acute CaMKII modulators, there were fewer aggresome-like structures containing iNOS. All of the treatments that chronically affected CaMKII activity or expression significantly inhibited iNOS-specific activity following cytokine induction. The results suggest that CaMKIIδ2 may be an important regulator of iNOS trafficking and activity in VSMCs.
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Yu, Xin, Liang Ge, Liang Niu, Xin Lian, Haichun Ma i Lei Pang. "The Dual Role of Inducible Nitric Oxide Synthase in Myocardial Ischemia/Reperfusion Injury: Friend or Foe?" Oxidative Medicine and Cellular Longevity 2018 (28.10.2018): 1–7. http://dx.doi.org/10.1155/2018/8364848.
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Nitric oxide synthases (NOSs) are a family of enzymes that are responsible for the synthesis of nitric oxide (NO) from the amino acid L-arginine in the body. Among the three key NOSs, the expression of inducible NOS (iNOS) can only be induced by inflammatory stimuli and contribute to the large amount of NO production. iNOS-derived NO plays an important role in various physiological and pathophysiological conditions, including the ischemic heart disease. Nowadays, the development of specific iNOS inhibitors and the availability of iNOS knockout mice have provided substantial evidence to support the role of iNOS/NO signaling in the myocardium. Nevertheless, the role of iNOS/NO signaling in the myocardial ischemic reperfusion injury is very complex and highly perplexing; both detrimental and beneficial effects of iNOS have been described. Thus, this review will aim at providing basic insights into the current progress of the role of iNOS in myocardial ischemia reperfusion injury. A better understanding of the dual role of iNOS in details may help facilitate the development of more effective therapies for the management of ischemic heart diseases.
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Bandyopadhyay, A., S. Chakder i S. Rattan. "Regulation of inducible and neuronal nitric oxide synthase gene expression by interferon-gamma and VIP". American Journal of Physiology-Cell Physiology 272, nr 6 (1.06.1997): C1790—C1797. http://dx.doi.org/10.1152/ajpcell.1997.272.6.c1790.
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The studies examined the regulation of inducible and neuronal nitric oxide synthases (iNOS and nNOS, respectively) in the rat brain, stomach, rectum, and spleen. Relative expression of iNOS and nNOS mRNAs was quantified by the sensitive method of polymerase amplification reactions. The NOS proteins were determined by Western blot, using specific antibodies. Highest levels of nNOS and iNOS mRNAs were expressed in the rat brain and spleen, respectively. Furthermore, both nNOS and iNOS were expressed in the stomach and rectum. Interestingly, treatment of tissues with lipopolysaccharides or cytokine interferon-gamma (IFN-gamma) induced the expression of iNOS and decreased that of nNOS, representing a shift from one isoform to the other. When the tissues were treated with IFN-gamma followed by vasoactive intestinal polypeptide (VIP), the induction of iNOS was reduced by VIP. The changes in iNOS and nNOS expression at the transcriptional level corresponded to those at the translational level. The data suggest a regulatory role of IFN-gamma and VIP in the expression iNOS and nNOS and a counterregulation of iNOS and nNOS in rat tissues.
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Zeng, Chenbo, i Aubrey R. Morrison. "Disruption of the actin cytoskeleton regulates cytokine-induced iNOS expression". American Journal of Physiology-Cell Physiology 281, nr 3 (1.09.2001): C932—C940. http://dx.doi.org/10.1152/ajpcell.2001.281.3.c932.
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Interleukin-1β (IL-1β) induces the inducible nitric oxide synthase (iNOS), resulting in the release of nitric oxide (NO) from glomerular mesangial cells. In this study, we demonstrated that disruption of F-actin formation by sequestration of G-actin with the toxin latrunculin B (LatB) dramatically potentiated IL-1β-induced iNOS protein expression in a dose-dependent manner. LatB by itself had little or no effect on iNOS expression. Staining of F-actin with nitrobenzoxadiazole (NBD)-phallacidin demonstrated that LatB significantly impaired F-actin stress fiber formation. Jasplakinolide (Jasp), which binds to and stabilizes F-actin, suppressed iNOS expression enhanced by LatB. These data strongly suggest that actin cytoskeletal dynamics regulates IL-1β-induced iNOS expression. We demonstrated that LatB decreases serum response factor (SRF) activity as determined by reporter gene assays, whereas Jasp increases SRF activity. The negative correlation between SRF activity and iNOS expression suggests a negative regulatory role for SRF in iNOS expression. Overexpression of a dominant negative mutant of SRF increases the IL-1β-induced iNOS expression, providing direct evidence that SRF inhibits iNOS expression.
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Gunnett, Carol A., Yi Chu, Donald D. Heistad, Angela Loihl i Frank M. Faraci. "Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase". American Journal of Physiology-Heart and Circulatory Physiology 275, nr 2 (1.08.1998): H416—H421. http://dx.doi.org/10.1152/ajpheart.1998.275.2.h416.
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The inducible isoform of nitric oxide synthase (iNOS) is expressed after systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nitric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient mice. We studied contraction of the carotid artery from wild-type and iNOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF2α (3–30 μM) and thromboxane A2 analog (U-46619; 3–100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generated by rings in response to PGF2α was 0.39 ± 0.02 and 0.25 ± 0.01 (SE) g ( n = 14) in vehicle and LPS-treated wild-type mice, respectively ( P < 0.001 vs. vehicle). Thus LPS reduced constrictor responses in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessels. Indomethacin also improved constrictor responses in arteries from wild-type mice injected with LPS. In contrast, contraction of the carotid arteries in response to PGF2α and U-46619 was not impaired in LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries from wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mice. These findings provide the first direct evidence that iNOS mediates impairment of vascular contraction after treatment with LPS.
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Vallance, Bruce A., Wanyin Deng, Myriam De Grado, Crystal Chan, Kevan Jacobson i B. Brett Finlay. "Modulation of Inducible Nitric Oxide Synthase Expression by the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium in Infected Mice". Infection and Immunity 70, nr 11 (listopad 2002): 6424–35. http://dx.doi.org/10.1128/iai.70.11.6424-6435.2002.
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ABSTRACT Citrobacter rodentium belongs to the attaching and effacing family of enteric bacterial pathogens that includes both enteropathogenic and enterohemorrhagic Escherichia coli. These bacteria infect their hosts by colonizing the intestinal mucosal surface and intimately attaching to underlying epithelial cells. The abilities of these pathogens to exploit the cytoskeleton and signaling pathways of host cells are well documented, but their interactions with the host's antimicrobial defenses, such as inducible nitric oxide synthase (iNOS), are poorly understood. To address this issue, we infected mice with C. rodentium and found that iNOS mRNA expression in the colon significantly increased during infection. Immunostaining identified epithelial cells as the major source for immunoreactive iNOS. Finding that nitric oxide (NO) donors were bacteriostatic for C. rodentium in vitro, we examined whether iNOS expression contributed to host defense by infecting iNOS-deficient mice. Loss of iNOS expression caused a small but significant delay in bacterial clearance without affecting tissue pathology. Finally, immunofluorescence staining was used to determine if iNOS expression was localized to infected cells by staining for the C. rodentium virulence factor, translocated intimin receptor (Tir), as well as iNOS. Interestingly, while more than 85% of uninfected epithelial cells expressed iNOS, fewer than 15% of infected (Tir-positive) cells expressed detectable iNOS. These results demonstrate that both iNOS and intestinal epithelial cells play an active role in host defense during C. rodentium infection. However, the selective expression of iNOS by uninfected but not infected cells suggests that this pathogen has developed mechanisms to locally limit its exposure to host-derived NO.
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Bae, Sang-Keun, Hey-Na Cha, Tae-Jin Ju, Yong-Woon Kim, Hee Sun Kim, Yong-Dae Kim, Jin-Myoung Dan, Jong-Yeon Kim, Se-dong Kim i So-Young Park. "Deficiency of inducible nitric oxide synthase attenuates immobilization-induced skeletal muscle atrophy in mice". Journal of Applied Physiology 113, nr 1 (1.07.2012): 114–23. http://dx.doi.org/10.1152/japplphysiol.00431.2011.
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The present study examined the effects of inducible nitric oxide synthase (iNOS) deficiency on skeletal muscle atrophy in single leg-immobilized iNOS knockout (KO) and wild-type (WT) mice. The left leg was immobilized for 1 wk, and the right leg was used as the control. Muscle weight and contraction-stimulated glucose uptake were reduced by immobilization in WT mice, which was accompanied with increased iNOS expression in skeletal muscle. Deficiency of iNOS attenuated muscle weight loss and the reduction in contraction-stimulated glucose uptake by immobilization. Phosphorylation of Akt, mTOR, and p70S6K was reduced to a similar extent by immobilization in both WT and iNOS KO mice. Immobilization decreased FoxO1 phosphorylation and increased mRNA and protein levels of MuRF1 and atrogin-1 in WT mice, which were attenuated in iNOS KO mice. Aconitase and superoxide dismutase activities were reduced by immobilization in WT mice, and deficiency of iNOS normalized these enzyme activities. Increased nitrotyrosine and carbonylated protein levels by immobilization in WT mice were reversed in iNOS KO mice. Phosphorylation of ERK and p38 was increased by immobilization in WT mice, which was reduced in iNOS KO mice. Immobilization-induced muscle atrophy was also attenuated by an iNOS-specific inhibitor N6-(1-iminoethyl)-l-lysine, and this finding was accompanied by increased FoxO1 phosphorylation and reduced MuRF1 and atrogin-1 levels. These results suggest that deficiency of iNOS attenuates immobilization-induced skeletal muscle atrophy through reduced oxidative stress, and iNOS-induced oxidative stress may be required for immobilization-induced skeletal muscle atrophy.
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HICKEY, Michael J. "Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment". Clinical Science 100, nr 1 (8.12.2000): 1–12. http://dx.doi.org/10.1042/cs1000001.
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Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesion of leucocytes in the microcirculation. However, during various types of inflammation, expression of the inducible form of nitric oxide synthase (iNOS) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in unstimulated tissue. Under these conditions, it is less well understood whether iNOS-derived nitric oxide retains the anti-adhesive capabilities of constitutively produced nitric oxide. This review summarizes work done to examine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endothelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experiments were extended by the advent of the iNOS-deficient (iNOS-/-) mouse. Intravital microscopy studies of these mice have indicated that, under conditions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leucocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other studies have observed either no effect or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Taken together, these studies suggest that the importance of iNOS in modulating leucocyte recruitment can vary according to the type of inflammatory response.
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Ye, Yumei, Juan D. Martinez, Regino J. Perez-Polo, Yu Lin, Barry F. Uretsky i Yochai Birnbaum. "The role of eNOS, iNOS, and NF-κB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin". American Journal of Physiology-Heart and Circulatory Physiology 295, nr 1 (lipiec 2008): H343—H351. http://dx.doi.org/10.1152/ajpheart.01350.2007.
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Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS−/− and iNOS−/− mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-κB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS−/− and iNOS−/− mice received ATV (10 mg·kg−1·day−1; ATV+) or water alone (ATV−) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-κB in WT mice. It also increased myocardial COX2 activity. In eNOS−/− mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-κB was not activated by ATV in the eNOS−/− mice. In the iNOS−/− mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-κB was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-κB, dependent. Activation of COX2 is dependent on iNOS.
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Jones, Steven P., James J. M. Greer, Paul D. Ware, Jiang Yang, Kenneth Walsh i David J. Lefer. "Deficiency of iNOS does not attenuate severe congestive heart failure in mice". American Journal of Physiology-Heart and Circulatory Physiology 288, nr 1 (styczeń 2005): H365—H370. http://dx.doi.org/10.1152/ajpheart.00245.2004.
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Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS−/−) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type ( n = 17), sham iNOS−/− ( n = 8), MI wild-type ( n = 56), and MI iNOS−/− ( n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 ± 2.0% and 441 ± 20 μl·min−1·g−1) and iNOS−/− (9.8 ± 1.3% and 471 ± 26 μl·min−1·g−1) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS−/− mice. None of the indexes demonstrated any significant differences between iNOS−/− and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.
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Zhang, Yan, Jun Yang, Li Zhuan, Guanghui Zang, Tao Wang i Jihong Liu. "Transplantation of adipose-derived stem cells overexpressing inducible nitric oxide synthase ameliorates diabetes mellitus-induced erectile dysfunction in rats". PeerJ 7 (12.08.2019): e7507. http://dx.doi.org/10.7717/peerj.7507.
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Background Erectile dysfunction is a major complication of diabetes mellitus. Adipose-derived stem cells (ADSCs) have attracted much attention as a promising tool for the treatment of diabetes mellitus-induced erectile dysfunction (DMED). Inducible nitric oxide synthase (iNOS) plays an important role in protecting penile tissues from fibrosis. The aim of this study was to determine the efficacy of ADSCs overexpressing iNOS on DMED in rats. Methods ADSCs were isolated and infected with adenovirus overexpressing iNOS (named as ADSCs-iNOS). The expression of iNOS was detected using western blot analysis and real-time PCR. Rats were randomly assigned into five groups: control group, DMED group, ADSCs group, ADSCs-EGFP group and ADSCs-iNOS group. 5 × 105 cells were given once via the intracorporal route. Two weeks after treatment, erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were obtained and evaluated at histology level. Results We found that ADSCs-iNOS had significantly higher expression of iNOS at mRNA and protein levels and generated more nitric oxide (NO). ADSCs-iNOS reduced collagen I and collagen IV expression of corpus cavernosum smooth muscle cells (CCSMCs) in cell co-culture model. Transforming growth factor-β1 expression in CCSMCs reduced following co-culture with ADSCs-iNOS. Injection of ADSCs-iNOS significantly ameliorated DMED in rats and decreased collagen/smooth muscle cell ratio of penile tissues. Moreover, elevated NO and cyclic guanosine monophosphate concentrations were detected in penile tissues of ADSCs-iNOS group. Conclusion Taken together, ADSCs-iNOS significantly improved erectile function of DMED rats. The therapeutic effect may be achieved by increased NO generation and the suppression of collagen I and collagen IV expression in the CCSMCs to decrease penile fibrosis.
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Webber, Robert, Richard Sweet i Douglas Webber. "Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations". International Journal of Molecular Sciences 22, nr 24 (13.12.2021): 13371. http://dx.doi.org/10.3390/ijms222413371.
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To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan–Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb’s efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship.
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Huo, Li-Jun, Cheng-Guang Liang, Ling-Zhu Yu, Zhi-Sheng Zhong, Zeng-Ming Yang, Heng-Yu Fan, Da-Yuan Chen i Qing-Yuan Sun. "Inducible nitric oxide synthase-derived nitric oxide regulates germinal vesicle breakdown and first polar body emission in the mouse oocyte". Reproduction 129, nr 4 (kwiecień 2005): 403–9. http://dx.doi.org/10.1530/rep.1.0542.
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The present study investigated the subcellular localization of inducible nitric oxide synthase (iNOS) during mouse oocyte meiotic maturation and fertilization using confocal microscopy, and further studied the roles of iNOS-derived NO in oocyte maturation by using an iNOS-specific inhibitor aminoguanidine (AG) and iNOS antibody microinjection. In germinal vesicle-stage oocytes, iNOS immunoreactivity was mainly localized in the germinal vesicle. Shortly after germinal vesicle breakdown, the iNOS immunoreactivity accumulated around the condensed chromosomes. At metaphase I and metaphase II, with the organization of chromosomes to the equatorial plate, iNOS immunoreactivity was concentrated around the aligned chromosomes, putatively the position of the metaphase spindle. The accumulation of iNOS immunoreactivity could not be detected at anaphase I and anaphase II. However, at telophase I and telophase II, the staining of iNOS was concentrated in the region between the separating chromosomes/chromatids. Furthermore, the staining of iNOS also accumulated in the male and female pronuclei in fertilized eggs. Germinal vesicle breakdown and the first polar body emission of the oocytes were significantly blocked by the iNOS-specific inhibitor AG in a dose-dependent manner. The germinal vesicle breakdown in oocytes injected with iNOS antibody was also inhibited. We found that the phosphorylation of mitogen-activated protein kinase in oocytes after germinal vesicle breakdown was inhibited by AG treatment. The control oocytes extruded a normal first polar body, while the AG-treated oocytes exhibited an elongated protrusion or no elongated protrusion. The results of confocal microscopy showed that the AG-treated oocytes were arrested at anaphase I–telophase I. Our results suggest that the iNOS-derived NO pathway plays important roles in mouse oocyte meiotic maturation, especially in germinal vesicle breakdown and the anaphase–telophase transition.
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Kalk, Philipp, Dirk Westermann, Sophia Herzfeld, Katharina Relle, Thiemo Pfab, Christian Bauer, Carsten Tschöpe, Johannes-Peter Stasch i Berthold Hocher. "Additional lack of iNOS attenuates diastolic dysfunction in aged ET-1 transgenic miceThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin." Canadian Journal of Physiology and Pharmacology 86, nr 6 (czerwiec 2008): 353–57. http://dx.doi.org/10.1139/y08-032.
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Endothelin-1 (ET-1) exhibits potent proinflammatory and profibrotic properties. Moreover, inflammation is a potent stimulus for inducible NO synthase (iNOS), which has been shown to contribute to cardiac injury. We thus hypothesized that ET-1-induced cardiac injury is attenuated by concomitant lack of iNOS. We established crossbred animals of ET-1 transgenic mice (ET+/+) and iNOS knockout mice (iNOS−/−). At 13 months of age, mice were allocated according to their genotype to one of 4 study groups: wild type (WT) controls (n = 8); ET-1 transgenic (ET+/+) mice (n = 10); iNOS knockout (iNOS−/−) mice (n = 7); and crossbred (ET+/+ iNOS−/−) mice (n = 15). Left ventricular function was determined in vivo by using a tip catheter. Animals were subsequently euthanized and hearts were harvested for weight assessment and histologic evaluation. No cardiac hypertrophy was present, as evidenced by similar mean cardiac weight and myocyte diameter in all groups. Cardiac perivascular fibrosis was significantly increased in ET+/+ and iNOS−/− groups versus WT, whereas ET+/+ iNOS−/− mice did not differ from WT. Regarding left ventricular function, plasma B-type natriuretic peptide was elevated in ET+/+ and iNOS−/− mice, but again in crossbred animals this effect was blunted. Heart catheterization revealed a significantly increased stiffness constant in both ET-overexpressing groups versus WT, but this increase was significantly attenuated in the ET+/+iNOS−/− group versus the ET+/+ group. Parameters indicating systolic heart failure (EF, cardiac output), however, were not different between all study groups. Our study demonstrates that ET transgenic mice develop left ventricular stiffening with subsequent diastolic dysfunction in a slow, age-dependent manner. Additional knock out of iNOS significantly attenuates cardiac injury. We thus conclude that ET-1-induced cardiac injury is at least partially mediated by iNOS.
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Yu, Zhiyuan, Xuefeng Xia i Bruce C. Kone. "Expression profile of a human inducible nitric oxide synthase promoter reporter in transgenic mice during endotoxemia". American Journal of Physiology-Renal Physiology 288, nr 1 (styczeń 2005): F214—F220. http://dx.doi.org/10.1152/ajprenal.00258.2004.
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Inducible nitric oxide synthase (iNOS) is involved in many physiological and pathophysiological processes, including septic shock and acute kidney failure. Little is known about transcriptional regulation of the human iNOS gene in vivo under basal conditions or in sepsis. Accordingly, we developed transgenic mice carrying an insertional human iNOS promoter-reporter gene construct. In these mice, the proximal 8.3 kb of the human iNOS 5′-flanking region controls expression of the reporter gene of enhanced green fluorescent protein (EGFP). Patterns of human iNOS promoter/EGFP transgene expression in tissues were examined by fluorescence microscopy and immunoblotting. Endogenous murine iNOS was basally undetectable in kidney, intestine, spleen, heart, lung, liver, stomach, or brain. In contrast, EGFP from the transgene was basally expressed in kidney, brain, and spleen, but not the other tissues of the transgenic mice. Bacterial lipopolysaccharide induced endogenous iNOS expression in kidney, intestine, spleen, lung, liver, stomach, and heart, but not brain. In contrast, human iNOS promoter/EGFP transgene expression was induced above basal levels only in intestine, spleen, brain, stomach, and lung. Within kidney, human iNOS promoter/EGFP fluorescence was detected most prominently in proximal tubules of the outer cortex and collecting ducts and colocalized with endogenous mouse iNOS. Within the collecting duct, both endogenous iNOS and the human iNOS promoter/EGFP transgene were expressed in cells lacking aquaporin-2 immunoreactivity, consistent with expression in intercalated cells. Although it remains possible that essential regulatory elements reside in remote locations of the gene, our data concerning this 8.3-kb region provide the first in vivo evidence suggesting differential transcriptional control of the human iNOS gene in these organs and marked differences in transcriptional regulatory regions between the murine and human genes.
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Li, Qianhong, Yiru Guo, Wei Tan, Qinghui Ou, Wen-Jian Wu, Diana Sturza, Buddhadeb Dawn, Greg Hunt, Chuanjue Cui i Roberto Bolli. "Cardioprotection Afforded by Inducible Nitric Oxide Synthase Gene Therapy Is Mediated by Cyclooxygenase-2 via a Nuclear Factor-κB–Dependent Pathway". Circulation 116, nr 14 (2.10.2007): 1577–84. http://dx.doi.org/10.1161/circulationaha.107.689810.
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Background— Gene therapy with inducible nitric oxide synthase (iNOS) markedly reduces myocardial infarct size; this effect is associated with cyclooxygenase-2 (COX-2) upregulation and is ablated by COX-2 inhibitors. However, pharmacological inhibitors are limited by relative lack of specificity; furthermore, the mechanism whereby iNOS gene therapy upregulates COX-2 remains unknown. Accordingly, we used genetically engineered mice to test the hypothesis that the cardioprotection afforded by iNOS gene transfer is mediated by COX-2 upregulation via a nuclear factor (NF)-κB–dependent pathway. Methods and Results— Mice received an intramyocardial injection of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 3 days later, myocardial infarction was produced by a 30-minute coronary occlusion followed by 4 hours of reperfusion. Among Av3/LacZ-treated mice, infarct size was similar in COX-2 −/− and wild-type groups. iNOS gene transfer (confirmed by iNOS immunoblotting and activity assays) markedly reduced infarct size in wild-type mice but failed to do so in COX-2 −/− mice. In transgenic mice with cardiac-specific expression of a dominant-negative mutant of IκBα (IκBα S32A,S36A ), the upregulation of phosphorylated IκBα, activation of NF-κB, and cardiac COX-2 protein expression 3 days after iNOS gene therapy were abrogated, which was associated with the abolishment of the cardioprotective effects afforded by iNOS gene therapy. Conclusions— These data provide strong genetic evidence that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection and that NF-κB is a critical link between iNOS and COX-2. Thus, iNOS imparts its protective effects, at least in part, by recruiting NF-κB, leading to COX-2 upregulation. However, COX-2 does not play an important cardioprotective role under basal conditions (when iNOS is not upregulated).
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Luo, Suxin, Tingting Wang, Honghua Qin, Han Lei i Yong Xia. "Obligatory role of heat shock protein 90 in iNOS induction". American Journal of Physiology-Cell Physiology 301, nr 1 (lipiec 2011): C227—C233. http://dx.doi.org/10.1152/ajpcell.00493.2010.
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Inducible nitric oxide (NO) synthase (iNOS) plays an important role in cell injury and host defense. While undetectable in normal tissues, iNOS expression is induced by endotoxins and inflammatory cytokines primarily via the IκB kinase/nuclear factor-κB (IKK-NF-κB) and Janus kinase (JAK)-signal transducers and activators of transcription 1 (STAT1) pathways. Our previous studies found that heat shock protein 90 (Hsp90) associates with iNOS, and this association enhances iNOS activity. Here we show that Hsp90 is also essential for iNOS induction. With mouse macrophages, Hsp90 inhibition by geldanamycin or knockdown with small interfering RNA (siRNA) prevented lipopolysaccharide (LPS) or interferon-γ (IFN-γ)-stimulated iNOS protein expression. RT-PCR experiments showed that iNOS mRNA transcription was blocked by Hsp90 inhibition. Radicicol, another Hsp90 inhibitor whose structure is different from that of geldanamycin, also blocked iNOS mRNA transcription. These cell biology findings were confirmed in infarcted myocardium where iNOS expression was markedly attenuated by Hsp90 inhibition in vivo. Intriguingly, further analyses showed that inhibiting Hsp90 had no significant effect on the activation of either IKK-NF-κB or JAK-STAT1 in LPS/IFN-γ-stimulated cells. Neither was the nuclear transport of active NF-κB or STAT1 affected by Hsp90 inhibition. But Hsp90 inhibition markedly reduced the binding of active NF-κB and STAT1 to their DNA elements. Chromatin immunoprecipitation assays confirmed that Hsp90 was essential for NF-κB and STAT1 bindings to iNOS promoters inside cells. These studies reveal that besides acting as an allosteric enhancer, Hsp90 is also required for transcriptional factor binding amid iNOS mRNA transcription. In view of the essential role of Hsp90 in iNOS gene transactivation, targeting Hsp90 may represent a new approach to intervene iNOS expression in diseases.
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Vodovotz, Y., N. S. Kwon, M. Pospischil, J. Manning, J. Paik i C. Nathan. "Inactivation of nitric oxide synthase after prolonged incubation of mouse macrophages with IFN-gamma and bacterial lipopolysaccharide." Journal of Immunology 152, nr 8 (15.04.1994): 4110–18. http://dx.doi.org/10.4049/jimmunol.152.8.4110.
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Abstract Large amounts of nitric oxide (NO) are produced by the inducible isoform of NO synthase (iNOS) in many cell types once the iNOS gene is transcriptionally activated. In primary mouse peritoneal macrophages elicited by thioglycolate broth, expression of iNOS follows treatment with IFN-gamma and is synergistically increased by the addition of bacterial LPS. Expression of iNOS is suppressible at transcriptional and translational levels by certain cytokines and microbial products. The present study describes a novel form of inactivation of iNOS that is post-translational and nondegradative. Mouse peritoneal macrophages cultured in the presence of IFN-gamma alone or IFN-gamma plus LPS rapidly depleted the medium of L-arginine, a substrate for iNOS, and stopped producing NO. Repletion of L-arginine permitted cells treated with IFN-gamma alone to resume NO production for at least 5 days, leading to the release of more NO than macrophages were previously believed capable of generating. L-Arginine repletion also boosted NO production by macrophages cultured for up to 2 to 3 days in the presence of IFN-gamma plus LPS, but thereafter, iNOS was inactive in these cells whether or not L-arginine was repleted. Activity of iNOS could be restored by adding both L-arginine and fresh IFN-gamma with or without LPS, likely reflecting the synthesis of new enzyme. However, the inactivation of iNOS seen late in culture with a single application of IFN-gamma plus LPS could be attributed neither to loss of iNOS protein nor to its autoinactivation by NO. Thus, LPS, a co-inducer of iNOS, causes macrophages to inactivate iNOS about 3 days after the onset of its induction. The mechanism, which remains to be identified, is novel for iNOS, in that it decreases neither its amount nor its apparent molecular mass.
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Greenberg, Stan S., Xinfang Zhao, Ji-Fang Wang, Li Hua i Jie Ouyang. "cAMP and purinergic P2yreceptors upregulate and enhance inducible NO synthase mRNA and protein in vivo". American Journal of Physiology-Lung Cellular and Molecular Physiology 273, nr 5 (1.11.1997): L967—L979. http://dx.doi.org/10.1152/ajplung.1997.273.5.l967.
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Adenosine 3′,5′-cyclic monophosphate (cAMP) and purinergic P2y receptor agonists upregulate inducible nitric oxide (NO) synthase (iNOS) but inhibit Escherichia coli endotoxin lipopolysaccharide (LPS)- and cytokine-mediated upregulation of iNOS in cultured cells. We examined the effects of cAMP and P2y receptor agonists on the iNOS system in vivo. Intratracheal administration of dibutyryl-cAMP (DBcAMP, 0.1 and 1 mg/kg), a P2y receptor agonist [2-methylthioadenosine 5′-triphosphate (MeS-ATP), 5 mg/kg], or LPS (0.6 mg/kg) to rats 2 h before bronchoalveolar lavage (BAL) increased iNOS mRNA (competitor-equalized reverse transcription-polymerase chain reaction) and iNOS protein (Western blot) in rat alveolar macrophages compared with the effects of sterile phosphate-buffered saline (0.5 ml it). At equal levels of upregulation of iNOS mRNA, 1) LPS, but not DBcAMP or MeS-ATP, upregulated nuclear transcription factor-κB (NF-κB) and 2) iNOS protein and formation of NO were greater in alveolar macrophages from LPS- and MeS-ATP-treated rats than from DBcAMP-treated rats. Administration of DBcAMP or MeS-ATP 15 min before LPS did not inhibit LPS-induced alveolar macrophage-derived iNOS mRNA, iNOS protein, and NO. Diethyldithiocarbamate (DETC, 5 mg/kg it) inhibited LPS-induced iNOS mRNA but did not affect upregulation of iNOS mRNA produced by the other agonists. We conclude that an LPS-dependent and -independent pathway of iNOS mRNA induction exists in vivo. The former is activated by LPS and most cytokines, is associated with upregulation of NF-κB and inhibited by DETC, and elicits an inflammatory response. The latter, activated by DBcAMP and MeS-ATP, is not associated with upregulation of NF-κB, inhibition by DETC, or activation of inflammation. The two systems are additive in vivo rather than antagonistic. Speculatively, if the LPS-independent iNOS pathway exists in humans, the iNOS in tissues from patients taking drugs affecting cAMP or P2y receptors may be iatrogenic rather than pathogenetic in origin.
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Zhang, Liping, Huanyu Wang, Mei Feng i Xueqing Zhang. "Bioinformatics analysis of the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses". Pteridines 31, nr 1 (30.07.2020): 142–50. http://dx.doi.org/10.1515/pteridines-2020-0019.
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AbstractObjective To evaluate the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses.Methods IiNOS/NOS2 expression in tumor and corresponding normal tissues of glioma patients was analyzed using the TCGA database and the online analysis tool GEPIA. The mutation statuses of iNOS/NOS2 genes were also explored in the TCGA database using cBioPortal. Co-expressed genes relevant to iNOS/NOS2 were screened by LinkedOmics. Gene ontology (GO) and KEGG pathway enrichment for iNOS/NOS2 and co-expressed genes was performed using LinkedOmics. Overall survival (OS) and disease-free survival (DFS) outcomes between iNOS/NOS2 mRNA high and low expression groups were compared using a log-rank test. Twenty-two glioma patients who underwent operation were included in the present work. A real-time PCR assay was used to detect iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissue.Results There was no statistical difference in iNOS/NOS2 mRNA expression levelss between tumor and normal tissues of glioma. A real-time PCR assay indicated that iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissues were not statistical difference (p>0.05). A mutation rate of 0.8% for the iNOS/NOS2 gene was found using 1044 glioma patients from two datasets. The mutation types include deep deletion (0.4%), truncating (0.2%) and missense (0.2%). The top positive and negative co-expressed gene with iNOS/NOS2 were COL25A1 (rpearson=0.4734, p<0.05) and ALCAM (rpearson=0.4734, p<0.05), respectively. For KEGG pathway analysis, iNOS/NOS2 was mainly enriched in calcium signaling pathway, Wnt signaling pathway, GnRH signaling pathway, HIF-1 signaling pathway and pathways in cancer. The overall survival (HR=2.0, p<0.05) and disease-free survival (HR=1.6, p<0.05) values were significantly different between iNOS/NOS2 high and low expression groups.Conclusion OS and DFS were significantly decreased in high iNOS/NOS2 mRNA expression groups. iNOS/NOS2 can be used as a poor prognostic biomarker for glioma.
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Porst, Markus, Andrea Hartner, Holger Krause, Karl F. Hilgers i Roland Veelken. "Inducible nitric oxide synthase and glomerular hemodynamics in rats with liver cirrhosis". American Journal of Physiology-Renal Physiology 281, nr 2 (1.08.2001): F293—F299. http://dx.doi.org/10.1152/ajprenal.2001.281.2.f293.
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This study was designed to test the hypothesis that glomerular de novo expression of inducible nitric oxide synthase (iNOS) contributes to renal hemodynamic abnormalities in liver cirrhosis developed 3 wk after common bile duct ligature (CBDL). De novo expression of iNOS mRNA was detected by RT-PCR in RNA extracts from isolated CBDL rat glomeruli whereas no iNOS mRNA was found in control rat glomerular RNA. Immunohistochemical staining for iNOS was negative in control animals whereas, in CBDL rats, positive iNOS staining was detected in an apparently mesangial pattern in all glomeruli. Western blots of protein extracts from isolated glomeruli of CBDL rats, but not control animals, showed a prominent iNOS band of 130 kDa. Mean arterial pressure (MAP), renal plasma flow (RPF; p-aminohippurate clearance), and glomerular filtration rate (GFR; inulin clearance) were unaltered in CBDL rats, but the application of 4 mg/kgl- N(6)-(1-iminoethyl)lysine, a specific inhibitor of iNOS, reduced GFR and RPF significantly in CBDL rats, whereas control animals were not affected. Similar results were obtained with lipopolysaccharide (LPS)-pretreated animals, which were studied as a positive control for iNOS expression and as a model for recent iNOS induction. We conclude that de novo expression of iNOS occurs in glomeruli of rats with liver cirrhosis and that nitric oxide, generated by iNOS, contributes to the maintenance of glomerular filtration in the early state of this disease.