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

Shah, Vijay H.; Cao, Sheng; Hendrickson, Helen; Yao, Jingwen; Katušić, Zvonimir S.

doi:10.1152/ajpgi.2001.280.6.g1209

Cited by 93 publications

(100 citation statements)

References 33 publications

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“…This finding was expected in animals with chronic liver injury and has been documented by others. 7,19 However, when ADMA was added, in BDE rats the pre-existing endothelial dysfunction was further aggravated and resulted in paradoxical vasoconstriction, which is in agreement with an environment where vasoconstrictors highly upregulated 1,24,29,30 and where an already dysfunctional eNOS is impeded further or even completely inhibited. In contrast, in TAAinduced rats with cirrhosis the decreased vasorelaxing capacity was not impaired further, which supports the hypothesis of a decreased eNOS enzyme level as a causative factor.…”

Section: Discussionsupporting

confidence: 62%

“…Theoretically, eNOS malfunction might result from either a direct inhibition of eNOS or indirect through dysfunctional cofactors. Shah and colleagues 19,27 provided support for the latter hypothesis by demonstrating that enhanced hepatic caveolin-1 protein levels in rats with BDE-induced cirrhosis may mediate reduced NOS activity, since NOS activity was partially restored when excess calmodulin, a protein that competitively binds eNOS, was added to the liver.…”

Section: Discussionmentioning

confidence: 98%

“…The conversion of L-3 H-arginine to L-3 H-citrulline was used as an index of NOS activity. A previously described method 19 was applied with slight modifications. Briefly, fresh liver was homogenized in a sucrose buffer at a final concentration of 0.2 g wet weight of liver/mL.…”

Section: Methodsmentioning

confidence: 99%

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A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Laleman¹,

Omasta²,

Casteele³

et al. 2005

Hepatology

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Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]-induced and bile duct excision [BDE]-induced, n ‫؍‬ 10 each), one rat model of PHT without cirrhosis (partial portal vein-ligated [PPVL], n ‫؍‬ 10), and sham-operated control rats (n ‫؍‬ 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration-effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAAor BDE-induced cirrhosis (n ‫؍‬ 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA-induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE-induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium-dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by N G -nitro-L-arginine-methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell-mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% ؎ 6.0% vs. 70.9% ؎ 3.2%). In conclusion, in rats with TAA-induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity. (HEPATOLOGY 2005;42:1382-1390

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Laleman¹,

Omasta²,

Casteele³

et al. 2005

Hepatology

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“…Primary HSCs were isolated and cultured from normal Fisher rats, as previously described in detail. 18 HSC cell purity was confirmed by: (1) immunocytochemical expression of ␣-SMA after several days in culture, (2) lack of expression of eNOS by Western blot analysis of HSC lysates, and (3) characteristic phase contrast morphology. Isolated primary HSCs were resuspended in culture media, plated on plasticware, and activated.…”

Section: Methodsmentioning

confidence: 99%

Proteasome inhibition induces hepatic stellate cell apoptosis

et al. 2006

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“…More recently in cholestatic models of disease, the upregulation of sinusoidal caveolin-1 and a decrease in eNOS activity is seen (Shah et al 2001). Most importantly, elevated expression of caveolin-1 has been found in patients with hepatocellular carcinoma and hepatitis C related cirrhosis suggesting that the upregulation of caveolin-1 may be contribute to endothelial dysfunction in the liver (Yokomori et al 2002(Yokomori et al , 2003.…”

Section: Regulation Of No Production By Protein-protein Interactions mentioning

confidence: 99%

Regulation of endothelial derived nitric oxide in health and disease

Sessa

2005

Mem. Inst. Oswaldo Cruz

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In the past decade the importance of the vascular endothelium as a multifunctional regulator of vascular smooth muscle physiology and pathophysiology has been appreciated. Indeed, the endothelium responds to hemodynamic stimuli (pressure, shear stress, and wall strain) and locally manufactured mediators (such as bradykinin, prostaglandins, and angiotensin) and in turn can release factors that can influence the adhesion and aggregation of circulating cells to the endothelium and the tone of vascular smooth muscle. In many diseases, including atherosclerosis, diabetes or cirrhosis endothelial dysfunction manifested as an impairment nitric oxide (NO) production or bioactivity may be an early hallmark of disease and a treatable entity. In this chapter, the importance of NO as a mediator of vascular function and potential mechanisms of endothelial NO synthase (eNOS) activation in disease will be discussed. Regulation of vascular tone by endogenous NOeNOS is the NOS isoform responsible for producing the classical endothelium-derived relaxing factor as originally described by (Furchgott & Zawadski 1981). Evidence for the importance of eNOS derived NO in the regulation of vascular tone is based on experiments in animals and in humans demonstrating that L-arginine based inhibitors of NOS increase blood or perfusion pressure and vascular resistance and reduce blood flow in vivo and in vitro. More recently, this has been unequivocally confirmed using mice with targeted disruption of the eNOS gene locus. eNOS knockout mice (-/-) are mildly hypertensive relative to wild-type littermate control mice (+/+) of the same generation. Importantly, the pressor effect of nitro-L-arginine, a NOS inhibi- tor, is attenuated in the -/-mice and endothelium-dependent relaxation in response to acetylcholine is abrogated in isolated vessels (Huang et al. 1995, Shesely et al. 1996. This fundamental finding is direct "proof of-principal" for the major contribution of NO in vasomotor control in large blood vessels. Physiological activation of eNOS and NO releaseTypically, endothelial cells release NO in response to autacoids that mobilize intracellular calcium such as thrombin, VEGF or ADP. The proposed mechanism for eNOS activation is that the released calcium will bind to calmodulin (CaM) and the calcium/CaM complex will bind to the CaM site in the enzyme promote NO synthesis. However, the most physiological agonist for NO release is fluid shear stress. Shear stress in vitro or shear rate in vivo, is the tangential vector of force elicited by the flow of blood over the endothelial cell surface. Exposure of endothelial cells to shear stress results in a burst of NO release, followed by a sustained phase. In vivo, increasing shear rate due to high blood flow will cause flow dependent dilations of certain vascular beds while decreasing shear rate will promote vasoconstriction. Shear induced NO release in vitro and flow-dependent vasodilation in vivo can be blocked with NOS inhibitors. Interestingly, shearinduced NO release appears to "independen...

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

Cited by 93 publications

References 33 publications

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Proteasome inhibition induces hepatic stellate cell apoptosis

Regulation of endothelial derived nitric oxide in health and disease

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