Disease relevance of Nos3

• Intravenous infusion of wild-type progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization of Nos3(-/-) mice in a model of hind-limb ischemia, suggesting that progenitor mobilization from the bone marrow is impaired in Nos3(-/-) mice [1].
• Cardiac deletion of GC-A did not affect arterial hypertension but significantly exacerbated cardiac hypertrophy and fibrosis in eNOS-/- mice [2].
• Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo [3].
• This study provides the first demonstration of a proinflammatory role of vascular eNOS in sepsis [4].
• Notably, eNOS-/- mice exhibit markedly increased cardiac ANP levels, suggesting that increased activation of cardiac GC-A can prevent hypertensive heart disease [2].

Psychiatry related information on Nos3

• Adult WT and eNOS(-/-) mice were subjected to sham operation or bilateral castration to induce vasculogenic erectile dysfunction [5].
• Furthermore, during long-term retention and reversal learning, eNOS-/- mice showed improved performance [6].
• Physical activity significantly increased Sol weight by 22% (P < 0.05) in WT but not eNOS-/- mice [7].
• We conclude that exposure to mild hypoxia during a critical period of lung development impairs alveolarization and reduces vessel density in the eNOS-deficient mouse [8].

High impact information on Nos3

• Nitric oxide (NO) production by endothelial cell nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension [9].
• Thus, an important mechanism underlying impaired activity of eNOS in injured sinusoidal endothelial cells is defective phosphorylation of Akt caused by overexpression of GRK2 after injury [9].
• Mechanistically, matrix metalloproteinase-9 (MMP-9), which is required for stem cell mobilization, was reduced in the bone marrow of Nos3(-/-) mice [1].
• Mice treated with oestrogen show increased eNOS activity and decreased vascular leukocyte accumulation after ischaemia and reperfusion injury [10].
• Thus eNOS mediates basal vasodilation [11].

Chemical compound and disease context of Nos3

• These findings suggest that (1) not only iNOS but also eNOS is up-regulated in the acute phase of experimental bacterial meningitis, and (2) iNOS-derived NO contributes to peroxynitrite formation and BBB breaching in this disease [12].
• In addition, eNOS knockout mice with unilateral ureteral obstruction were given tap water or L-arginine supplemented water to drink and sacrificed after 14 days [13].
• In eNOS knockout mice with unilateral ureteral obstruction for 14 days L-arginine supplementation had no effect on pelvic urine nitrite levels and did not alter renal histopathology or cortical thickness [13].
• In summary, isoproterenol or high Ca(2+) pretreatment increased ischemia-reperfusion injury in males more than females. eNOS expression and NO production were higher in female than male hearts, and L-NAME blocked female protection [14].
• S-methyl-L-thiocitrulline (SMLT), a selective neuronal and endothelial NOS inhibitor was started 24 hours before ureteral obstruction and administered to half of the study animals [13].

Biological context of Nos3

• Until 17 days of gestation, litter size did not differ between both genotypes, but at birth the number of viable newborn pups and their weights were smaller in Nos3-/- than in Nos3+/+ mice [15].
• We conclude that Nos3 and Agt are important genes in the regulation of blood pressure during pregnancy [16].
• The negative effect of Nos3 deficiency on ovulatory capacity and early embryonic development is modulated by genetic background [17].
• The gene encoding endothelial nitric oxide synthase, Nos3, maps to rat chromosome 4 [18].
• These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability [19].

Anatomical context of Nos3

• RESULT(S): The mean number of oocytes was significantly reduced in Nos3 deficient mice on a C57BL/6J background compared with controls [17].
• Oocytes deficient for Nos3 on a C57BL/6J background also showed reduced progression to two-cell stage embryos after 24 hours, two-cell stage embryos to blastocyst stage embryos, and survival to 48 hours [17].
• Furthermore, in human umbilical vein endothelial cells, LPS leads to the activation of eNOS through phosphoinositide 3-kinase- and Akt/protein kinase B-dependent enzyme phosphorylation [3].
• Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes [20].
• Herein, bone marrow-derived macrophages (BMDMØs) from wild-type and endothelial NOS (eNOS) knock-out (KO) mice have been used to assess the role of this constitutive NOS isoform in the regulation of macrophage activation [21].

Associations of Nos3 with chemical compounds

• In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles [22].
• Nitric oxide (NO) produced by the constitutive NO synthase (cNOS) in neurons has been implicated in mediating excitotoxic neuronal death [23].
• Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice [24].
• BMDMØs from eNOS KO animals exhibited reduced nuclear factor-kappaB activity, iNOS expression, and NO production after exposure to lipopolysaccharide (LPS) as compared with cells derived from wild-type mice [21].
• The aim of this study was to investigate the regulation of endothelial nitric oxide synthase (eNOS) activity by acute and chronic elevated glucose [25].
• These data demonstrate a novel role of Ang II in diabetic uncoupling of eNOS and that Ang II-targeted therapy improves endothelial function via the novel mechanism of recoupling eNOS [26].

Physical interactions of Nos3

• In addition, the molecular chaperone Hsp90 interacts with eNOS and positively regulates eNOS activity [27].

Enzymatic interactions of Nos3

• The serine/threonine protein kinase Akt (protein kinase B) phosphorylates endothelial cell nitric oxide synthase (eNOS) and enhances its ability to generate nitric oxide (NO) [28].

Regulatory relationships of Nos3

• Grafts from iNOS KO mice served as a second group of controls where the contribution from iNOS was eliminated but eNOS was preserved [29].
• We hypothesized that tPA induces an inhibition of endothelial NO synthase (eNOS) after focal ischemia that is responsible for ischemic damage and may be restored by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [30].
• In the mesenteric arteries the expression of nox4 (4 weeks) and gp91phox (nox2) (8 weeks) subunits of NADPH oxidase from streptozotocin-apoE(-/-) were enhanced as were eNOS mRNA and protein (P<0.05) [31].
• The increased expression and phosphorylation of eNOS with RPM appears to be regulated by mechanisms other than Akt or Caveolin-1 [32].
• Iso-stimulated ventricular relaxation is also enhanced in the eNOS-/- mice, as measured by dP/dt(min) in the isolated heart [33].

Other interactions of Nos3

• VEGF superfusion significantly increased permeability in both WT and iNOS(-/-) mice but not in eNOS(-/-) mice [19].
• These data indicate that NO plays a role in modulating insulin sensitivity and carbohydrate metabolism and that the eNOS isoform may play a dominant role relative to nNOS [34].
• Intriguingly, similar levels of arterial hypertension are accompanied by marked cardiac hypertrophy in GC-A-/-, but not in eNOS-/-, mice, suggesting that changes in local pathways regulating cardiac growth accelerate cardiac hypertrophy in the former and protect the heart of the latter [2].
• CONCLUSIONS: The overexpression of TGF-beta1 and eNOS may represent mechanisms in iNOS-KO mice to compensate for their loss of functional iNOS, resulting in incisional wound healing equivalent to controls [35].
• In eNOS knockout animals, tPA again significantly increased infarct size after transient focal ischemia [30].

Analytical, diagnostic and therapeutic context of Nos3

• Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = eNOS(-/-) with l-NIL [19].
• The expression and activity of eNOS were measured using quantitative PCR and nitrite measurements respectively [25].
• Immunoblotting and in-cell Western blot analysis were employed to assess changes in VEGF receptor signaling pathway and eNOS phosphorylation of ser1177 [36].
• By use of reverse transcription-polymerase chain reaction analysis, immunohistochemistry, and Western blotting, increased brain mRNA and increased protein levels of endothelial NOS (eNOS) and iNOS were detected 24 h after intracisternal pneumococcal inoculation [12].
• However, the functional importance of endothelial NOS (eNOS) in the rejecting allografts remains unclear [29].

References