Overexpressed nitric oxide synthase in portal-hypertensive stomach of rat: A key to increased susceptibility to damage?

Ohta, Masayuki; Tanoue, Kazuo; Tarnawski, A; Pai, Rama; Itani, R.; Sander, FC; Sugimachi, Keizō; Sarfeh, I. James

doi:10.1053/gast.1997.v112.pm9178684

Cited by 57 publications

(68 citation statements)

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“…We have previously shown by immunofluorescence staining that eNOS 12 and TNF-␣ 13 expression is predominantly colocalized to the endothelia of the mucosal and submucosal vessels in PHT gastric mucosa. However, because PI 3-K-Akt signaling takes place in most cell types and is not exclusive to endothelial cells, in the present study we investigated the effects of TNF-␣ on PI 3-kinase and Akt activation in normal RGM1 cells.…”

Section: Discussionmentioning

confidence: 91%

“…So far, increased eNOS activity has been thought to be caused by increased eNOS protein levels in the PHT vasculature and gastric mucosa. 12,36,37 However, the molecular events and signaling mechanisms leading to eNOS activation in portal hypertension and PHT gastropathy remain unknown. In some vessels, other than those of the gastrointestinal tract, transient activation of eNOS by an increase in cytosolic Ca 2ϩ induced by agonists results in short-term NO production, leading to temporary vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…First, the increased TNF-␣ up-regulates the expression and activity of eNOS, which likely results in increased cytotoxicity to the gastric mucosa and increased susceptibility to injury owing to excessive NO production giving rise to free-radical formation and peroxynitrite production. 12 Second, the increased TNF-␣ likely increases the permeability of the PHT microvasculature and may also be involved in the morphologic changes resulting in the microvascular abnormalities of PHT gastropathy. 13 Furthermore, the role of TNF-␣ and NO overproduction in the increased susceptibility to injury is indicated by the fact that anti-TNF-␣ antibody and Nnitro-L-arginine methyl ester (L-NAME), respectively, reversed the increased susceptibility to injury produced by ethanol.…”

Section: Discussionmentioning

confidence: 99%

“…13 Furthermore, the role of TNF-␣ and NO overproduction in the increased susceptibility to injury is indicated by the fact that anti-TNF-␣ antibody and Nnitro-L-arginine methyl ester (L-NAME), respectively, reversed the increased susceptibility to injury produced by ethanol. 12,13 Although gastric TNF-␣ is elevated in portal vein-stenosed rats, the mechanism of this change remains unclear because it is well established that plasma TNF-␣ concentrations are normal in portal hypertension and increase in relation to the severity of liver disease. However, the fact that TNF-␣ levels are elevated in pa- 44 This requirement also renders eNOS calcium dependent.…”

Section: Discussionmentioning

confidence: 99%

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Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

et al. 2002

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Activation of endothelial nitric oxide synthase (eNOS) in portal hypertensive (PHT) gastric mucosa leads to hyperdynamic circulation and increased susceptibility to injury. However, the signaling mechanisms for eNOS activation in PHT gastric mucosa and the role of TNF-␣ in this signaling remain unknown. In PHT gastric mucosa we studied (1) eNOS phosphorylation (at serine 1177) required for its activation; (2) association of the phosphatidylinositol 3-kinase (PI 3-kinase), and its downstream effector Akt, with eNOS; and, (3) whether TNF-␣ neutralization affects eNOS phosphorylation and PI 3-kinase-Akt activation. To determine human relevance, we used human microvascular endothelial cells to examine directly whether TNF-␣ stimulates eNOS phosphorylation via PI 3-kinase. PHT gastric mucosa has significantly increased (1) eNOS phosphorylation at serine 1177 by 90% (P < .01); (2) membrane translocation (P < .05) and phosphorylation (P < .05) of p85 (regulatory subunit of PI 3-kinase) by 61% and 85%, respectively; (3) phosphorylation (P < .01) and activity (P < .01) of Akt by 40% and 52%, respectively; and (4) binding of Akt to eNOS by as much as 410% (P < .001). Neutralizing anti-TNF-␣ antibody significantly reduced p85 phosphorylation, phosphorylation and activity of Akt, and eNOS phosphorylation in PHT gastric mucosa to normal levels. Furthermore, TNF-␣ stimulated eNOS phosphorylation in human microvascular endothelial cells. In conclusion, these findings show that in PHT gastric mucosa, TNF-␣ stimulates eNOS phosphorylation at serine 1177 (required for its activation) via the PI 3-kinase-Akt signal transduction pathway. (HEPATOLOGY 2002;35: 393-402.) P ortal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. Gastric hemorrhage-either spontaneous or caused by noxious agents such as alcohol and nonsteroidal anti-inflammatory drugs-occurs in ϳ30% of patients with PHT gastropathy. 1-3 Clinical and experimental data including our own indicate that compared with normal gastric mucosa, the PHT gastric mucosa has increased susceptibility to injury. 1,3-5 The microvascular abnormalities have been implicated in the increased susceptibility of PHT gastric mucosa to damage. [4][5][6][7][8] Excessive production of nitric oxide (NO) by endothelial NO synthase (eNOS) has been suggested as the basis for the systemic hyperdynamic and abnormal circulation of PHT gastric mucosa. [9][10][11][12] Tumor necrosis factor ␣ (TNF-␣) has been shown indirectly to be a major contributor to the hyperdynamic circulation likely through activation of NO synthase. [13][14][15] However, direct evidence for this has been lacking. Our previous study showed that elevated TNF-␣ up-regulates eNOS expression and its enzymatic activity in PHT gastric mucosa and that neutralization of TNF-␣ reverses the hemodynamic abnormalities of PHT gastric mucosa. 13 Although these data clearly indicate that TNF-␣ is involved in the activation of eNOS in PHT gastric mucosa, the molecular mechanisms and signaling pathways of eNOS a...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

et al. 2002

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“…[4][5][6][7][8][9] We have recently showed that nitric oxide synthase isoform 3 (NOS3) messenger RNA (mRNA) and protein are overexpressed in PHT gastric mucosa of rats, and this overexpression may be, at least in part, responsible for the increased susceptibility of PHT gastric mucosa to damage. 10 However, the mechanisms that activate NOS3 in PHT gastric mucosa are unknown.…”

mentioning

confidence: 99%

Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

et al. 1998

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Anti-tumor necrosis factor ␣ (TNF-␣) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-␣ is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-␣ treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-␣ and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-␣-neutralizing antibody treatment. The TNF-␣ protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-␣ antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-␣ may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-␣ treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa. (HEPATOLOGY 1998;27: 906-913.)Portal hypertensive (PHT) gastropathy is now recognized as a clinical entity that is frequently seen in patients with portal hypertension. 1-3 The PHT gastric mucosa has distinct morphological and functional abnormalities that increase its susceptibility to damage by noxious factors such as alcohol, aspirin, and ischemia/reperfusion. [4][5][6][7][8][9] We have recently showed that nitric oxide synthase isoform 3 (NOS3) messenger RNA (mRNA) and protein are overexpressed in PHT gastric mucosa of rats, and this overexpression may be, at least in part, responsible for the increased susceptibility of PHT gastric mucosa to damage. 10

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Duration of the Hemodynamic Effects of NG-Nitro-l-arginine Methyl Ester in Vivo

Conner¹,

Aiko²,

Fernández³

et al. 2000

Nitric Oxide

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Overexpressed nitric oxide synthase in portal-hypertensive stomach of rat: A key to increased susceptibility to damage?

Cited by 57 publications

References 3 publications

Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

Duration of the Hemodynamic Effects of NG-Nitro-l-arginine Methyl Ester in Vivo

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