Tumor necrosis factor α: A major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats

López-Talavera, Juan Carlos; Merrill, William; Groszmann, Roberto J.

doi:10.1016/0016-5085(95)90449-2

Cited by 181 publications

(97 citation statements)

References 32 publications

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“…85 However, there are some pieces of evidence supporting the role of iNOS in mediating the hyperdynamic circulation in cirrhotic rats with ascites; first, mRNA transcripts for iNOS in arterial vessels are increased 86 ; second, iNOS immunostaining is present in the smooth muscle of arterial vessels; third, anti-TNF antibodies ameliorate the hemodynamic disturbances observed in cirrhotic rats. 94,95 However, the presence of eNOS in the arteries of the PVL rat and cirrhotic rat, as well as the recent findings that eNOS is induced by shear stress and mechanical forces, leads to the question of the relative roles of the two NOS isoforms. 84,86 In cirrhotic rats with ascites, iNOS protein can also be demonstrated histochemically in the renal glomeruli and in peritoneal macrophage isolated from ascites fluid.…”

Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 99%

The hepatic circulation in health and disease: Report of a single-topic symposium

et al. 1998

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Section: Pathogenesis Of Portal Hypertensionmentioning

confidence: 99%

The hepatic circulation in health and disease: Report of a single-topic symposium

et al. 1998

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“…[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.…”

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confidence: 99%

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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“…Besides endotoxins, the other possible factors stimulating NO production include cytokines such as TNF-α, IL-1, IL-6, and IFN-γ [22][23][24] Among these, TNF-α has been studied the most. LopezTalavera et al found that anti-TNF-α antibody increases mean arterial pressure and systemic vascular resistance, and decreases cardiac index and portal pressure [25] . In our 4-week BDL rats, in parallel with increased serum TNF-α, aortic NOS3 expression and serum nitrate/nitrite concentrations were increased [26] .…”

Section: Endocannabinoidsmentioning

confidence: 99%

Cardiac and vascular changes in cirrhosis: Pathogenic mechanisms

Liu

Gaskari²,

Lee

2006

WJG

130

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Cardiovascular abnormalities accompany both portal hypertension and cirrhosis. These consist of hyperdynamic circulation, defined as reduced mean arterial pressure and systemic vascular resistance, and increased cardiac output. Despite the baseline increased cardiac output, ventricular inotropic and chronotropic responses to stimuli are blunted, a condition known as cirrhotic cardiomyopathy. Both conditions may play an initiating or aggravating pathogenic role in many of the complications of liver failure or portal hypertension including ascites, variceal bleeding, hepatorenal syndrome and increased postoperative mortality after major surgery or liver transplantation. This review briefly examines the major mechanisms that may underlie these cardiovascular abnormalities, concentrating on nitric oxide, endogenous cannabinoids, central neural activation and adrenergic receptor changes. Future work should address the complex interrelationships between these systems.

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Tumor necrosis factor α: A major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats

Cited by 181 publications

References 32 publications

The hepatic circulation in health and disease: Report of a single-topic symposium

The hepatic circulation in health and disease: Report of a single-topic symposium

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

Cardiac and vascular changes in cirrhosis: Pathogenic mechanisms

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