Oxygen regulation of rat hepatocyte iNOS gene expression

Vargiu, Cristina; Belliardo, Sabina; Cravanzola, Carlo; Grillo, M.A.; Colombatto, Sebastiano

doi:10.1016/s0168-8278(00)80217-2

Cited by 27 publications

(9 citation statements)

References 22 publications

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“…Moreover, it is now recognized that iNOS expression is induced by hypoxia (37,73), which occurs from both acute and chronic alcohol exposure (2,3). It is possible that in our model SAM inhibited the alcohol-mediated increase in iNOS by modulation of hypoxia in the liver.…”

Section: ⅐ϫmentioning

confidence: 88%

S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver

Bailey¹,

Robinson²,

Pinner³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

105

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An early event that occurs in response to alcohol consumption is mitochondrial dysfunction, which is evident in changes to the mitochondrial proteome, respiration defects, and mitochondrial DNA (mtDNA) damage. S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive oxygen/nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial superoxide production, mtDNA damage, and inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of oxidant damage, SAM prevented alcohol-mediated losses in cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury: mitochondria dysfunction.

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Section: ⅐ϫmentioning

confidence: 88%

S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver

Bailey¹,

Robinson²,

Pinner³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

105

View full text Add to dashboard Cite

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“…In this latter study (40), hypoxia actually decreased IL-1 ␤ -mediated iNOS changes. Similar discrepancies exist in hepatocytes (41,42). Alternatively, hypoxia has been shown to increase iNOS expression in tumor cells (43) and not to affect endotoxin-or IFN-␥ -induced increases in iNOS mRNA in mesangial (44) or aortic smooth muscle cells (45).…”

Section: Hypoxic Regulation Of Inosmentioning

confidence: 71%

Complex Regulation of iNOS in Lung

Pitt

Croix

2002

Am J Respir Cell Mol Biol

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In a remarkably short period after the identification of nitric oxide (NO) as a novel signaling molecule in mammalian physiology, the critical role of L-arginine biosynthetic pathway in lung function became apparent (1). Numerous cell types within rodent and human lung (2) expressed one or more of the three known nitric oxide synthases (NOS) that catalyzed the five-electron oxidation of the N-terminal guanidino group of L-arginine to NO. The second of these oxidoreductases to be cloned (NOS2) is more commonly referred to as iNOS as a reflection of its unique features, including its ( 1 ) activation being independent of transient increases in intracellular calcium; and ( 2 ) inducibility at a transcriptional level in response to inflammatory or immunologic stimuli (3). The fundamental role of iNOS-derived NO in host defense contributed to the extraordinary large number of investigations into its regulation at transcriptional and post-transcriptional levels (4). Concurrent with these advances in iNOS regulation was an increasing awareness of the role of hypoxia in gene expression; and, thus, it is not surprising that these two areas of study have intersected. In this issue, Zulueta and colleagues (5) report that although hypoxia per se does not affect iNOS expression in cultured rat pulmonary microvascular endothelial cells, it does modulate IL-1 ␤ and TNF-␣ induction of iNOS at pretranscriptional through post-transcriptional levels. The study underscores the complexity of iNOS regulation and provides important observations that can be used to assess cell-, stimulus-, and species-specific differences in such regulation. iNOS in LungKobzik and coworkers (2) originally systematically localized iNOS in fixed tissue of rat and human lung. Immunoreactive iNOS was most apparent in rat alveolar macrophage after LPS and occasionally in human macrophage and endothelium in areas of chronic inflammation. Interestingly, both species showed immunoreactive iNOS in airway epithelium in normal tissue, suggesting the possibility of a constitutively active iNOS. Constitutively expressed iNOS in upper and lower airway epithelium was subsequently confirmed by Asano and coworkers (6) and Guo and colleagues (7). These latter investigators noted that this unusual expression was lost when human airway epithelium was cultured (8); and progress has been made in identifying a soluble, heat labile, acid insensitive autocrinederived mediator that accounts for such expression (9). The role of iNOS-derived NO and secondary reactive nitrogen intermediates in normal lung is unclear, but may be an important component of host defense (3), as well as a source of NO for S-nitrosylation of hemoglobin during its transpulmonary passage (10).The contribution of intrapulmonary iNOS-derived NO in experimental acute and chronic lung injury has been revealed by pharmacologic and genetic studies. Our laboratory has shown that exposure to mixtures of cytokines and endotoxin of cultured rat type II cells (11) and pulmonary artery (12) or intra-acinar (13) vascul...

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“…Plasma [NO X ], a biomarker of NO production, was not increased in rats treated with MCT, suggesting that inducible NOS (iNOS) was not upregulated. This was somewhat unexpected, considering that upregulation of iNOS in the liver accompanies a variety of stresses (Clemens, 1999;Hon et al, 2002), and hypoxia is a stimulus for iNOS transcription in HPCs (Vargiu et al, 2000). Furthermore, iNOS is often upregulated during inflammatory conditions, and in an earlier study, the plasma concentrations of several markers of inflammation were increased by MCT treatment .…”

Section: Discussionmentioning

confidence: 94%