Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats

Abraldes, Juan G.; Rodríguez–Vilarrupla, Aina; Graupera, Mariona; Zafra, Carmen; García‐Calderó, Héctor; García‐Pagán, Juan Carlos; Bosch, Jaime

doi:10.1016/j.jhep.2007.01.020

Cited by 220 publications

(188 citation statements)

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“…12,19,27,36 These kinds of drugs have been described as prophylactic agents to treat I/R injuries. 37 Moreover, we recently suggested that simvastatin could be used as a supplement for organ preservation solutions due to its capability to sustain the expression of KLF2-derived vasoprotective transcriptional pathways in cold-stored endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (HEPATOLOGY 2012;55:921-930)

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Section: Discussionmentioning

confidence: 99%

“…Levels of cGMP, a marker of NO bioavailability, were analyzed in liver homogenates using an enzyme immunoassay (Cayman Chemical, Ann Arbor, MI) as described. 19 The results are expressed as pmol/ mg tissue.…”

Section: Methodsmentioning

confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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“…There are other post translational regulations with the increase of translational nuclear factor "Krupper-like 2" (KLF-2), important to the transcription of endothelium protecting genes. This way, statins improve the flow mediated by vasodilation of intrahepatic vascularization in and reduces the post prandial HVPG [4,9,10].…”

Section: Statinsmentioning

confidence: 99%

“…In this context, statin seems a very attractive option since can interacts at the endothelium without the deleterious systemic effects seen with angiotensin converting enzyme inhibitors and others vasodilators [2]. The systemic effect of vasodilation is poorly tolerated and frequently leads to the drug suspension [3,4].…”

Section: Introductionmentioning

confidence: 99%

Statins in Cirrhotic Portal Hypertension – A Brief Review

Pollo-Flores¹,

Roever²

2016

Evidence Based Medicine and Practice

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Nowadays the cirrhosis physiopatology is being deeply studied and new pharmacology approach comes with new perspective of changing natural history and initial steps of the disease. The statins have many properties in this sense. These drugs have demonstrated effects improving portal hypertension, liver functions, hepatocellular carcinoma with few side effects. Its action mechanism happens predominantly in intrahepatic environment, what seems very attractive. Some studies were conducted in animals and very few in human beings. This brief review aim to address advantages of the use of statins in liver disease. One question still open is which statin is the best in liver disease and which population of cirrhotic profit the most of the drug.

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“…3 Following studies have unraveled the molecular basis of the statinderived liver protection demonstrating that statins regulate the expression of different genes and proteins that globally protect the unhealthy liver. 4,5 Particularly, statins activate the transcription factor Kruppel-like factor 2 (KLF2) that precisely orchestrates a variety of vasoprotective pathways. 6,7 It is important to denote that not all statins confer the same hepatic vasoprotection; indeed simvastatin and mevastatin are the most effective (Marrone and Gracia-Sancho, unpubl.…”

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confidence: 99%