Caveolin-1 in normal and cirrhotic human liver

Chatila, Rajaa; Theise, N; Shah, Vijay H.; West, A. B.; Sessa, William C.; Groszmann, Roberto J.

doi:10.1016/s0016-5085(00)86060-6

Cited by 6 publications

(5 citation statements)

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“…Increases in caveolin expression were associated with enhanced caveolin binding with eNOS, diminished NO production, and impaired hepatic vasodilatory responses in this model (32). Additionally, preliminary studies suggest a similar paradigm in human cirrhosis (4). In the present study, hepatic NOS activity is also diminished in the BDL model of portal hypertension in conjunction with enhanced caveolin expression.…”

Section: Discussionsupporting

confidence: 67%

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Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats

Shah

Cao

Hendrickson

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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In carbon tetrachloride-induced liver cirrhosis, diminution of hepatic endothelial nitric oxide synthase (eNOS) activity may contribute to impaired hepatic vasodilation and portal hypertension. The mechanisms responsible for these events remain unknown; however, a role for the NOS-associated proteins caveolin and calmodulin has been postulated. The purpose of this study is to characterize the expression and cellular localization of the NOS inhibitory protein caveolin-1 in normal rat liver and to then examine the role of caveolin in conjunction with calmodulin in regulation of NOS activity in cholestatic portal hypertension. In normal liver, caveolin protein is expressed preferentially in nonparenchymal cells compared with hepatocytes as assessed by Western blot analysis of isolated cell preparations. Additionally, within the nonparenchymal cell populations, caveolin expression is detected within both liver endothelial cells and hepatic stellate cells. Next, studies were performed 4 wk after bile duct ligation (BDL), a model of portal hypertension characterized by prominent cholestasis, as evidenced by a significant increase in serum cholesterol in BDL animals. After BDL, caveolin protein levels from detergent-soluble liver lysates are significantly increased as assessed by Western blot analysis. Immunoperoxidase staining demonstrates that this increase is most prominent within sinusoids and venules. Additionally, caveolin-1 upregulation is associated with a significant reduction in NOS catalytic activity in BDL liver lysates, an event that is corrected with provision of excess calmodulin, a protein that competitively binds eNOS from caveolin. We conclude that, in cholestatic portal hypertension, caveolin may negatively regulate NOS activity in a manner that is reversible by excess calmodulin.

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Section: Discussionsupporting

confidence: 67%

“…Caveolin-1 has been implicated as a negative regulator of eNOS activity (4,21,22). The findings in this study demonstrate that caveolin expression in liver vasculature is increased after BDL, a model of portal hypertension characterized by prominent cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats

Shah

Cao

Hendrickson

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Transduction of these cells is particularly intriguing, because these cells contain the downstream signaling targets, including soluble guanylate cyclase, necessary to influence vascular tone in response to NO as well as other vasodilator molecules such as CO (14,15,19,26,28). We and others (3,22,23,31) have previously demonstrated that caveolin-1 protein abundance is increased in cholestatic and noncholestatic models of chronic liver injury and cirrhosis within liver endothelial cells and that this may contribute to deficient hepatic eNOS activity in these models. The mechanism of caveolin upregulation remains uncertain but does not appear to be secondary to bile acids, at least as evidenced by a lack of bile acidmediated stimulation of caveolin promoter activity as assessed by a reporter assay in transfected cells (S. Cao and V. Shah, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously demonstrated that increased expression and eNOS binding of caveolin-1 in liver endothelial cells may contribute to deficient eNOS function in the BDL rat (22) and in human cirrhosis (3,31). Because hepatic stellate cells constitute an important target for the vasoregulatory effects of NOS-encoding adenoviral vectors (33), we wondered whether inhibitory signaling events in stellate cells may contribute to deficient function of heterologously expressed recombinant S1179DeNOS.…”

Section: S1179denos Improves Vasodilatory Responses In Sham Rats Butmentioning

confidence: 99%

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

Hendrickson

Chatterjee

Cao

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

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“…10 Intriguingly, the expression of the inhibitory binding protein caveolin-1 was found to be markedly increased in sinusoidal endothelial cells of cirrhotic livers. Because this increase has been confirmed in cirrhotic livers from patients suffering from hepatitis C or primary biliary cirrhosis, 67 caveolin-1 may well be a major mediator of reduced eNOS-activity deteriorating endothelial NOrelease in chronic liver disease.…”

Section: Increased Lipidperoxidationmentioning

confidence: 91%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002

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C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

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Caveolin-1 in normal and cirrhotic human liver

Cited by 6 publications

References 0 publications

Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats

Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

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