Liver eNOS Research Articles

Oleuropein ameliorates arsenic induced oxidative stress in mice

The objective of this study is to investigate the potential preventive effect of oleuropein in an experimental arsenic toxicity in mice. For this purpose, mice were exposed to 5mg/kg/day sodium arsenite (NaAsO2) in drinking water and treated with 30mg/kg/day oleuropein for 15 days. At the end of the experiment, animals were sacrificed and selected organs were processed for biochemical and histopahtological investigations. Blood, liver, kidney and brain malondialdehyde (MDA) and nitric oxide (NO) levels were determined by colorimetric methods. Protein carbonyl content is measured by a commercial kit. Liver morphology and immunoreactivity for inducible NOS (iNOS) and endothelial NOS (eNOS) was evaluated microscopically. Level of NO was determined to decrease in blood and tissues whereas MDA increased in arsenic given mice. Tissue protein carbonyl content also increased in this group. Immunoreactivity for iNOS and eNOS was noted to increase with arsenic treatment. Oleuropein treatment had significant effects in normalizing the MDA and NO levels as well as protein carbonyl content. Immunohistochemical staining also showed reduction of the expression of iNOS and eNOS in liver. The results indicate that oleuropein ameliorates oxidative tissue damage by scavenging free radicals.

Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis.

Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.

The Role of e-NOS in Chronic Cholestasis-Induced Liver and Renal Injury in Rats: The Effect of N-Acetyl Cysteine.

Introduction. The role of chronic cholestasis (CC) in liver injury and fibrosis remains unclear. The aims of this study were to define the role of endothelial nitric oxide synthase (e-NOS) in CC and the protective effect of N-acetyl-L-cysteine (NAC) in liver and kidney injury. Materials and Methods. Group A (sham group); Group B (CBDL); and Group C (CBDL + NAC). Group C received daily dosage of NAC (100 mg/kg) intraperitoneally for up to 4 weeks. Results. The rate of bridging fibrosis was higher (100% versus 20%, P = .025), but the intensity of e-NOS in liver was lower in rats that received NAC (1.3 versus 2.7, P = .046). The necrotic area in the kidneys among rats that received NAC was lower at week 4 (48% versus 57%; P < .001). The numbers of e-NOS stained cells in kidney were similar in sham group and the two groups with CBDL. Discussion. NAC reduced the stimulus for liver fibrosis in this rat model of CC and attenuated liver and kidney injury. Our study showed that e-NOS expression increased in liver tissue of rats with CC and that this was reversed by NAC. Treatment with NAC might restore e-NOS protein expression and prevent liver injury in CC.

Quercetin/adenosine combination may induce insulin resistance in high fat diet-fed mice

Quercetin and adenosine are natural antioxidants separately claimed to improve metabolic syndrome parameters. The effect of this combination (QA) was examined in high fat diet-fed mice. Results showed that growth and blood parameters, as observed for quercetin-treated mice, were not significantly different from the control. Adenosine alone caused hyperglycemia and reduced plasma adiponectin. QA feeding led to increased adiposity and circulatory insulin, and concomitantly down-regulated liver eNOS and LFABP expressions. This showed that interaction occurred between quercetin and adenosine, and combined ingestion may lead to insulin resistance, while adenosine does not prevent the development of metabolic syndrome.:

Downregulation of eNOS in a nutritional model of fatty liver

Summary Background & aims Fatty liver, inflammation, fibrosis and cirrhosis are associated with portal hypertension. Nitric oxide (NO) is a universal messenger molecule that plays diverse and essential physiological roles in multiple organ systems. A decrease in NO production can lead to disruption in blood flow and portal hypertension. We therefore sought to evaluate the in vivo effect of lipid accumulation in the liver on NO production, endothelial nitric oxide synthase (eNOS) expression and liver function. Methods Rats were intravenously infused with lipid emulsion (20% w/w triglycerides) for 1, 2, 4 and 6 days. Liver histology, blood parameters, and liver eNOS protein expression were studied. Results Histological evaluation and blood liver enzymes showed liver damage after 6 days of infusion, while a decrease in eNOS levels began at day 4. The latter was accompanied by an increase in 4-hydroxynonenal-protein adducts, a marker of oxidative stress. Conclusions These findings support the hypothesis that downregulation of eNOS in steatotic livers is an early event in non-alcoholic fatty liver disease progression.

Transcript Profiling Suggests That Differential Metabolic Adaptation of Mice to a High Fat Diet Is Associated with Changes in Liver to Muscle Lipid Fluxes

Genetically homogenous C57Bl/6 mice display differential metabolic adaptation when fed a high fat diet for 9 months. Most become obese and diabetic, but a significant fraction remains lean and diabetic or lean and non-diabetic. Here, we performed microarray analysis of "metabolic" transcripts expressed in liver and hindlimb muscles to evaluate: (i) whether expressed transcript patterns could indicate changes in metabolic pathways associated with the different phenotypes, (ii) how these changes differed from the early metabolic adaptation to short term high fat feeding, and (iii) whether gene classifiers could be established that were characteristic of each metabolic phenotype. Our data indicate that obesity/diabetes was associated with preserved hepatic lipogenic gene expression and increased plasma levels of very low density lipoprotein and, in muscle, with an increase in lipoprotein lipase gene expression. This suggests increased muscle fatty acid uptake, which may favor insulin resistance. In contrast, the lean mice showed a strong reduction in the expression of hepatic lipogenic genes, in particular of Scd-1, a gene linked to sensitivity to diet-induced obesity; the lean and non-diabetic mice presented an additional increased expression of eNos in liver. After 1 week of high fat feeding the liver gene expression pattern was distinct from that seen at 9 months in any of the three mouse groups, thus indicating progressive establishment of the different phenotypes. Strikingly, development of the obese phenotype involved re-expression of Scd-1 and other lipogenic genes. Finally, gene classifiers could be established that were characteristic of each metabolic phenotype. Together, these data suggest that epigenetic mechanisms influence gene expression patterns and metabolic fates.