Acute atorvastatin is hepatoprotective against ischaemia‐reperfusion injury in mice by modulating <scp>eNOS</scp> and microparticle formation

Ajamieh, Hussam; Farrell, Geoffrey C.; McCuskey, Robert S.; Yu, Jun; Chu, Eagle Sh; Wong, H.R.; Lam, Wesley; Teoh, Narci C.

doi:10.1111/liv.12827

Cited by 21 publications

(12 citation statements)

References 14 publications

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“…Even short-term therapy with ATV (5 mg/kg) just 1 h before ischemia in normal and steatotic mouse livers conferred a 70–90% reduction in post-I/R necrosis [23]. Other studies used varying dosages of statin pretreatment at varying time points and found similar effects in reduction of hepatopathology; these regimens included ATV pretreatment 10 mg/kg 24 h and again 1 h before ischemia induction, [33] Simvastatin (5 mg/kg) pretreatment 1 h before ischemia induction, [28] and Simvastatin (1 mg/kg) even 30 min before ischemia induction [21].…”

Section: Discussionmentioning

confidence: 99%

“…Key mechanisms include suppression of inflammation and microvascular protection. Statins reduce activity of signaling proteins Toll-like receptor-4 and High mobility group box 1 (HMGB1), translating to reduced activity of downstream inflammation mediator nuclear factor kappa B (NF-κB) as well as cytokines tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) [20, 23, 33]. Statins also upregulate endothelial nitric oxide synthase (eNOS) production [21, 24].…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively or additionally, cholestasis may have caused a pre-existent vasoconstrictive state that rendered the hepatic microcirculation unreceptive to ATV-mediated inhibition of vasoconstrictors (endothelin-1, thromboxane A2) and upregulation of NO, which would generally result in improved microcirculation, oxygen delivery, and energy metabolism. Also, the poor responsiveness to ATV treatment may have been exacerbated by the prevailing state of oxidative stress and sterile inflammation in cholestatic livers, [8] which cannot be fully resolved by HMGB-1, TLR4 and NF-κB inhibition with ATV [20, 23]. In light of the negative results, we chose not to further investigate the mechanisms that underlie the lacking therapeutic efficacy of ATV.…”

Section: Discussionmentioning

confidence: 99%

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Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

et al. 2017

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BackgroundExtrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury.MethodsMale Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis.ResultsI/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion.ConclusionPre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

et al. 2017

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“…While these findings are yet to be reproduced, other groups have instead begun to more comprehensively examine the profile of circulating EVs to better understand their temporal regulation, contents, and possible intervention strategies. Indeed it was shown that vesicles tend to increase on a background of NAFLD, and do so in a time-dependent manner, according to data obtained from flow cytometry experiments [ 74 , 75 , 76 ].…”

Section: Studies In Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

“…Conversely, exposing macrophages to such drugs may induce the release of EV-derived miRNAs, which suppress cancer growth by epigenetic regulation [ 57 ]. This concept has been extended to NAFLD models, where it was found that administering cholesterol-lowering drugs to high-fat fed rodents can attenuate the release of EVs, however the exact implication of this was not discussed, except for a potential reduction in liver cell death [ 73 , 74 ].…”

Section: Understanding the Role Of Secreted Vesiclesmentioning

confidence: 99%

Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease

Ban

Shackel

McLennan

2016

IJMS

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In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting.

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Extracellular Vesicles in Non-alcoholic Fatty Liver Disease: Key Players in Disease Pathogenesis and Promising Biomarker Tools

et al. 2020

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Acute atorvastatin is hepatoprotective against ischaemia‐reperfusion injury in mice by modulating eNOS and microparticle formation

Cited by 21 publications

References 14 publications

Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease

Extracellular Vesicles in Non-alcoholic Fatty Liver Disease: Key Players in Disease Pathogenesis and Promising Biomarker Tools

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