Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

Trebicka, Jonel; Hennenberg, Martin; Laleman, Wim; Shelest, Nataliya; Biecker, Erwin; Schepke, Michael; Nevens, Frederik; Sauerbruch, Tilman; Heller, J.

doi:10.1002/hep.21673

Cited by 278 publications

(364 citation statements)

References 51 publications

(78 reference statements)

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“…Thirty rats underwent bile duct ligation (BDL) to induce liver fibrosis as described 23, 24, 25. A mortality of 20% led to a total of 24 rats for assessment.…”

Section: Methodsmentioning

confidence: 99%

“…BDL rats were killed 2, 3, 4, 5, and 6 weeks after BDL (n = 5 per group, except for 4 weeks after BDL, n = 4). Blood was withdrawn and liver samples were cut into fragments and either snap frozen in liquid nitrogen and stored at –80°C or preserved in formaldehyde as described 11, 23, 24…”

Section: Methodsmentioning

confidence: 99%

“…Hepatic hydroxyproline was photometrically determined in liver hydrolysates 23, 24. Segments (200 mg) of snap‐frozen livers were hydrolyzed in HCl (6 N) at 110°C for 16 hours and filtered.…”

Section: Methodsmentioning

confidence: 99%

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Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Praktiknjo

Lehmann

Nielsen

et al. 2018

Hepatology Communications

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Patients with end‐stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute‐on‐chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro‐C3) and degradation (matrix metalloproteinase‐degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α‐smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro‐C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro‐C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1‐3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro‐C3 levels were associated with injury, disease severity scores (Model for End‐Stage Liver Disease, Child‐Pugh, chronic liver failure‐C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure‐C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211–222)

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“…Thirty rats underwent bile duct ligation (BDL) to induce liver fibrosis as described 23, 24, 25. A mortality of 20% led to a total of 24 rats for assessment.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Praktiknjo

Lehmann

Nielsen

et al. 2018

Hepatology Communications

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“…31,32 Therefore, we next examined the production of the vasoconstrictors and the response to them after intraperitoneal LPS pretreatment. LPS pretreatment augmented the generation of two relevant vasoconstrictors: TX and the Cys-LTs.…”

Section: Vasoconstrictor Production and Responsiveness After Lps Pretmentioning

confidence: 99%

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Steib¹,

Hartmann²,

Hesler³

et al. 2010

Laboratory Investigation

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Recent studies have shown that the risk of variceal bleeding in patients with liver cirrhosis increases with infections such as spontaneous bacterial peritonitis (SBP). In this study, we hypothesized that pretreatment with intraperitoneal LPS may escalate portal hypertension. In fibrotic livers (4 weeks after bile duct ligation, BDL), the activation of Kupffer cells (KCs) by zymosan (150 mg/ml) in the isolated non-recirculating liver perfusion system resulted in a transient increase in portal perfusion pressure. Pretreatment with intraperitoneal LPS (1 mg/kg body weight (b.w.) for 3 h) increased basal portal perfusion pressure, and prolonged the zymosan-induced increase from transient to a long-lasting increase that was sustained until the end of the experiments in BDL but not in sham-operated animals. Pretreatment with gadolinium chloride (10 mg/kg b.w.), MK-886 (0.6 mg/kg b.w.), Ly171883 (20 mM) or BM 13.177 (20 mM) reduced the maximal and long-lasting pressure increase in BDL animals by approximately 50-60%. The change in portal perfusion pressure was paralleled by a long-lasting production of cysteinyl leukotriene (Cys-LT) and thromboxane (TX) after LPS pretreatment. However, the response to vasoconstrictors was not altered by intraperitoneal LPS. Western blot analyses showed an increased Toll-like receptor (TLR)4 and MyD88 expression after LPS pretreatment. In vivo experiments confirmed that intraperitoneal LPS increased basal portal pressure, and extended the portal pressure increase produced by intraportal zymosan or by LPS infusion. In conclusion, upregulation of TLR4 and MyD88 expression in fibrotic livers confers hypersensitivity to LPS. This may lead to escalation of portal hypertension by production of TX and Cys-LT after endotoxin-induced KC activation. Therefore, LT inhibitors may represent a promising treatment option in addition to early administration of antibiotics in SBP.

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“…2,6,7 Statins have shown beneficial effects on hepatic fibrosis and portal hypertension in cirrhosis, most likely because the inhibition of HMG-CoA-reductase impedes small GTPases (RhoA and Ras). [8][9][10][11][12][13] The portal pressure-lowering effect was attributed to the inhibition of RhoA translocation to the membrane of myofibroblastic HSC and thereby disruption of RhoA/Rho-kinase signaling, resulting in decreased contraction of these cells and reduced intrahepatic resistance. 9 In a model of progressive biliary fibrosis using bile duct ligation (BDL) in rats, 14 prophylactic and early atorvastatin treatment attenuated activation of MFB and subsequent collagen deposition.…”

mentioning

confidence: 99%

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Klein

Klösel

Schierwagen

et al. 2012

Laboratory Investigation

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Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile ductligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10 À 4 , 10 À 5 and 10 À 6 M), transcription levels of profibrotic cytokines (transforming growth factor-b1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. a-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and b-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10 À 4 M and attenuated it at 10 À 5 M. Atorvastatin induced p21 protein expression and b-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells.

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Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

Cited by 278 publications

References 51 publications

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

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