Nitric oxide induces HIF-1α stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing

Riaño, Annia; Ortiz-Masiá, Dolores; Velázquez, Miriam; Calatayud, Sara; Esplugues, Juan V.; Barrachina, Dolores

doi:10.1007/s00535-011-0374-1

Cited by 18 publications

(12 citation statements)

References 40 publications

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“…Co-incubation (12 h) of CGS-21680 and L-NAME reduced the mRNA and protein levels of VEGF in normal cells, suggesting that VEGF expression is downstream of NO synthesis mediated by A 2A AR. The molecular mechanisms associated with VEGF expression mediated by NO are unclear, but since HIF is controlling the expression of VEGF, it is feasible that nitration of HIF is occurring in the human placenta, as has been described in jejunum extracted from rats [48].…”

Section: Discussionmentioning

confidence: 99%

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Escudero

Bertoglia

Hernadez

et al. 2012

Purinergic Signalling

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To investigate whether fetal endothelial cell proliferation and migration are modulated by the A 2A adenosine receptor (A 2A AR), nitric oxide (NO) and the vascular endothelial growth factor (VEGF) signaling pathway, we isolated human umbilical vein endothelial cells from normal pregnancy (n023), preterm delivery (n04), and late-onset (LOPE, n010) and early-onset preeclampsia (EOPE, n08). We used the non-selective adenosine receptor agonist (NECA) and the selective agonist (CGS-21680) and/or selective antagonist (ZM-241385) for A 2A AR. Also, the nitric oxide synthase (NOS) inhibitor, L-NAME, was used in co-incubation with CGS-21680. Compared to normal pregnancy, EOPE exhibited low cell proliferation and migration associated with reduced expressions of A 2A AR and VEGF and NO synthesis (i.e., total and phosphorylated serine 1177 endothelial NOS and nitrite formation). In contrast, LOPE exhibited the opposite behavior in all these markers compared to normal pregnancy or EOPE. Cell proliferation and migration were increased by CGS-21680 (or NECA) in all analyzed groups (EOPE>LO-PE>normal pregnancy) compared to their respective basal conditions, an effect that was associated with high NO and VEGF synthesis and blocked by ZM-241385 with significantly different IC 50 for each group (EOPE>LOPE>normal pregnancy). The differences seem independent of gestational age.L-NAME blocked the CGS-21680-mediated cell proliferation and migration in normal pregnancy and LOPE (IC 50 036.2± 2.5 and 8.6±2.2 nM, respectively) as well as the VEGF expression in normal pregnancy. Therefore, the A 2A AR/NO/ VEGF signaling pathway exhibits a pro-angiogenic effect in normal pregnancies and LOPE, whereas impairment in this pathway seems related to the reduced angiogenic capacity of the fetal endothelium in EOPE.

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Section: Discussionmentioning

confidence: 99%

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Escudero

Bertoglia

Hernadez

et al. 2012

Purinergic Signalling

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“…The implication of these alterations for feto-placental angiogenesis is poorly understood, but might involve changes in the activation of HIF (Kimura et al, 2002) and changes in the promoter activity of several proteins, including anti-angiogenic factors such as thrombospondin 2 (MacLauchlan et al, 2011) or pro-angiogenic factors like VEGF (Kimura et al, 2002; Feoktistov et al, 2004). Considering that NO can cause nitration of tyrosine residues on HIF-1α (Riano et al, 2011), and may contribute to stabilization, we propose that the reduced adenosine-mediated NO synthesis observed in EOPE might be associated with impaired HIF-dependent VEGF expression (see Figure 3 ). Clearly, more studies are necessary to understand all the processes involved in these alterations.…”

Section: Adenosine Angiogenesis and Preeclampsiamentioning

confidence: 98%

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

et al. 2014

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Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.

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“…Equal amounts of protein from macrophages or Caco-2 cells (nuclear, cytosolic or total extracts), 39,28 or from colonic tissues 40 were loaded onto SDS/PAGE gels and analyzed by western blot. Membranes were incubated overnight at 4 1C with different primary antibodies ( Table 2).…”

Section: Concomitant Medicationmentioning

confidence: 99%

Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD

et al. 2014

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A defective induction of epithelial autophagy may have a role in the pathogenesis of inflammatory bowel diseases. This process is regulated mainly by extracellular factors such as nutrients and growth factors and is highly induced by diverse situations of stress. We hypothesized that epithelial autophagy is regulated by the immune response that in turn is modulated by local hypoxia and inflammatory signals present in the inflamed mucosa. Our results reveal that HIF-1α and Wnt1 were co-localized with CD68 in cells of the mucosa of IBD patients. We have observed increased protein levels of β-catenin, phosphorylated mTOR, and p62 and decreased expression of LC3II in colonic epithelial crypts from damaged mucosa in which β-catenin positively correlated with phosphorylated mTOR and negatively correlated with autophagic protein markers. In cultured macrophages, HIF-1 mediated the increase in Wnt1 expression induced by hypoxia, which enhanced protein levels of β-catenin, activated mTOR, and decreased autophagy in epithelial cells in co-culture. Our results demonstrate a HIF-1-dependent induction of Wnt1 in hypoxic macrophages that undermines autophagy in epithelial cells and suggest a role for Wnt signaling and mTOR pathways in the impaired epithelial autophagy observed in the mucosa of IBD patients.

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Nitric oxide induces HIF-1α stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing

Abstract: These results suggest that iNOS-derived NO is involved in HIF-1α stabilization, probably through S-nitrosylation, and ITF expression in goblet cells of the damaged jejunum of indomethacin-treated rats and mediates ulcer healing.

Cited by 18 publications

References 40 publications

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD

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