Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

Moon, Kyung Ho; Hood, Brian L.; Mukhopadhyay, Partha; Rajesh, Mohanraj; Abdelmegeed, Mohamed A.; Kwon, Yong–Il; Conrads, Thomas P.; Veenstra, Timothy D.; Song, Byoung–Joon; Pacher, Pál

doi:10.1053/j.gastro.2008.06.048

Cited by 97 publications

(183 citation statements)

References 50 publications

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“…Indeed, several mitochondrial proteins, such as aldehyde dehydrogenase, are known to contain free sulfhydryl groups within their catalytic sites and are inactivated through S-nitrosylation (Moon et al, 2007;Andringa et al, 2008). Using an ischemia-reperfusion liver model, it was reported that ATP synthesis was markedly inhibited with the Snitrosylation of mitochondrial proteins such as 3-ketoacylCoA thiolase, and that pretreatment with a peroxynitrite scavenger restored enzyme activity and ATP synthesis (Moon et al, 2008). In addition, several key components of the mitochondrial respiration chain have altered function after their glutathionylation status has been changed (Beer et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Mouse Liver Protein Sulfhydryl Depletion after Acetaminophen Exposure

Yang

Greenhaw

Shi

et al. 2012

J Pharmacol Exp Ther

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Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries. This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose-dependent manner. Free protein sulfhydryls were measured in liver protein homogenates by labeling with maleimide linked to a near infrared fluorescent dye followed by SDS-polyacrylamide gel electrophoresis. Global protein sulfhydryl levels were decreased significantly (48.4%) starting at 1 hour after the APAP dose and maintained at this reduced level through 24 hours. To visualize the specific hepatocytes that had reduced protein sulfhydryl levels, frozen liver sections were labeled with maleimide linked to horseradish peroxidase. The centrilobular areas exhibited dramatic decreases in free protein sulfhydryls while the periportal regions were essentially spared. These protein sulfhydryl-depleted regions correlated with areas exhibiting histopathologic injury and APAP binding to protein. The majority of protein sulfhydryl depletion was due to reversible oxidation since the global-and lobule-specific effects were essentially reversed when the samples were reduced with tris(2-carboxyethy)phosphine before maleimide labeling. These temporal and zonal pattern changes in protein sulfhydryl oxidation shed new light on the importance that changes in protein redox status might play in the pathogenesis of APAP hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Mouse Liver Protein Sulfhydryl Depletion after Acetaminophen Exposure

Yang

Greenhaw

Shi

et al. 2012

J Pharmacol Exp Ther

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“…Because ALDH2 functions as an antioxidant enzyme, this protein may be easily inactivated by free radicals. Recently, ALDH2 was identified as a target for oxidative modification during glyceryl trinitrate tolerance (19,21) and hepatic ischemia-reperfusion (36). Therefore, oxidative modification of the thiol group may be responsible for ALDH2 inactivation under hyperglycemic conditions.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Aldehyde Dehydrogenase 2 by Oxidative Stress Is Associated with Cardiac Dysfunction in Diabetic Rats

Wang

Hao

et al. 2010

Mol Med

116

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Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with a-lipoic acid (α-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Δψ) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and α-LA attenuated these changes. Mitochondrial Δψ was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Δψ. The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats.

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“…The in vivo studies with the shorter methyl analogue, MnTM-4-PyP 5þ , were reported, presumably because of its commercial availability (191,223,224). With longer alkyl chains, bulkiness restrain toxic interactions with nucleic acids, whereas lipophilicity may compensate for the lower SOD-like activity.…”

Section: E Bioavailability Of Mn Porphyrinsmentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

467

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

Cited by 97 publications

References 50 publications

Mouse Liver Protein Sulfhydryl Depletion after Acetaminophen Exposure

Mouse Liver Protein Sulfhydryl Depletion after Acetaminophen Exposure

Inhibition of Aldehyde Dehydrogenase 2 by Oxidative Stress Is Associated with Cardiac Dysfunction in Diabetic Rats

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

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