Enhanced synthesis and reduced metabolism of endothelin-1 (ET-1) by hepatocytes - an important mechanism of increased endogenous levels of ET-1 in liver cirrhosis

Kuddus, Ruhul; Nalesnik, Michael A.; Субботин, Владимир; Rao, Abdul S.; Gandhi, Chandrashekhar R.

doi:10.1016/s0168-8278(00)80302-5

Cited by 53 publications

(37 citation statements)

References 40 publications

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“…Endothelin, apart from inducing myocardial hypertrophy, is also capable of inducing changes in ion currents in cardiomyocyte preparations in vitro [73]. Therefore, it is feasible that the elevated endothelin levels in cirrhosis [74] may also contribute to the electrophysiological changes in these patients. Increased bile acid levels in patients with biliary cirrhosis can affect membrane fluidity of myocytes, leading to the alteration of function of b-adrenoceptors, G protein, and ion channels [75] in patients with cholestasis.…”

Section: Electrophysiological Abnormalitiesmentioning

confidence: 99%

Cirrhotic cardiomyopathy

2008

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Cirrhotic cardiomyopathy is a recently recognized condition in cirrhosis consisting of systolic incompetence under condition of stress, diastolic dysfunction related to altered diastolic relaxation, and electrophysiological abnormalities in the absence of any known cardiac disease. It can be diagnosed by using a combination of electrocardiograph, 2-dimensional echocardiography, and various serum markers such as brain natriuretic factor. The underlying pathogenetic mechanisms include abnormalities in the b-adrenergic signaling pathway, altered cardiomyocyte membrane fluidity, increased myocardial fibrosis, cardiomyocyte hypertrophy, and ion channel defects. Various compounds for which levels are elevated in cirrhosis such as nitric oxide and carbon monoxide can also exert a negative inotropic effect on the myocardium, whereas excess sodium and volume retention can lead to myocardial hypertrophy. Various toxins can also aggravate the ion channel defects, thereby widening the QRS complex causing prolonged QT intervals. Clinically, systolic incompetence is most evident when cirrhotic patients are placed under stress, whether physical or pharmacological, or when the extent of peripheral arterial vasodilatation demands an increased cardiac output as in the case of bacterial infections. Acute volume overload such as immediately after insertion of a transjugular intrahepatic portosystemic shunt or after liver transplantation can also tip these cirrhotic patients into cardiac failure. Treatment of cirrhotic cardiomyopathy is unsatisfactory. There is some evidence that b-blockade may help some cirrhotic patients with baseline prolonged QT interval. Long-term aldosterone antagonism may help reduce myocardial hypertrophy. Future studies should include further elucidation of pathogenetic mechanisms so as to develop effective treatment strategies.

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Section: Electrophysiological Abnormalitiesmentioning

confidence: 99%

Cirrhotic cardiomyopathy

2008

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“…Hepatocytes were prepared as described previously [23], and suspended (0.25 × 10 6 cells/ml) in William's medium E supplemented with 2 mM L-glutamine, penicillin/streptomycin, 10% FBS, and 10 −6 M insulin. Cells were plated at a density of 0.063 × 10 6 /cm 2 , the medium renewed 3 h later, and the cells used following overnight incubation.…”

Section: Preparation Of Hepatocytesmentioning

confidence: 99%

Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

Thirunavukkarasu

Wang

Harvey

et al. 2008

Journal of Hepatology

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Background/Aims-Augmenter of liver regeneration (ALR), a protein synthesized and stored in hepatocytes, is associated with mitochondria, and possesses sulfhydryl oxidase and cytochrome c reductase activities. We sought to determine the effects of ALR depletion in hepatocytes by antisense oligonucleotide transfection.Methods-Rat hepatocytes in primary culture were transfected with antisense oligonucleotide for ALR mRNA (ALR-AS) or scrambled oligonucleotide. Various analyses were performed at times up to 24 h after transfection.Results-Treatment with ALR-AS caused a decrease in ALR mRNA, cellular depletion of ALR protein primarily from mitochondria, and decreased viability. Flow cytometric analysis of ALR-AStransfected hepatocytes stained with annexin-V cy3 and 7-aminoactinomycin D revealed apoptosis as the predominant cause of death up to 6 h; incubation beyond this time resulted in necrosis in addition to apoptosis. ALR-AS-transfection caused release of mitochondrial cytochrome c, activation of caspase-3, profound reduction in the ATP content, and cellular release of LDH. Inhibition of caspase-3 inhibited the early phase of ALR-AS-induced death but not the late phase that included ALR and LDH release.Conclusions-These results suggest that ALR is critically important for the survival of hepatocytes by its association with mitochondria and regulation of ATP synthesis. KeywordsAugmenter of liver regeneration; Antisense; Hepatocytes; Apoptosis; Necrosis ☆ The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research.

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“…18 75 77 Both ET A and ET B receptors were present on HSC and hepatocytes while only ET B receptors were present on sinusoidal endothelial cells and Kupffer cells. [78][79][80][81] "In cirrhotic patients, a direct relationship between ET-1 mRNA receptor abundance and the degree of portal hypertension has been documented" Compared with normal livers, the number of both ET receptors was increased in cirrhotic livers. 82 In cirrhotic patients, a direct relationship between ET-1 mRNA receptor abundance and the degree of portal hypertension has been documented.…”

Section: Vasoactive Substances Influencing Hsc Contractilitymentioning

confidence: 99%