Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat

Lehmann, Thorsten G.; Wheeler, Michael D.; Schwabe, Robert F.; Connor, Henry D.; Schoonhoven, Robert; Bunzendahl, H.; Brenner, David A.; Samulski, R. Jude; Zhong, Zhi; Thurman, Ronald G.

doi:10.1053/jhep.2000.19814

Cited by 77 publications

(51 citation statements)

References 35 publications

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“…36 On the other hand, intracellular expression of antioxidant enzymes, Cu/Zn-SOD and heme oxygenase-1, were protective in fatty liver transplants. 37,38 The survival results in preceding studies and our results show that to be effective, the antioxidants must be in intracellular location in adequate concentrations, in a timely manner.…”

Section: Discussionmentioning

confidence: 51%

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

2001

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Fatty livers in humans and rats are less tolerant of ischemia, endotoxin, and alcohol. We hypothesized that fatty livers of obese (Ob) Zucker rats are oxidatively stressed and oxidative stress could be relieved by antioxidant treatment, leading to improved tolerance to ischemia. Total glutathione (GSH), tocopherol (TOC), ascorbic acid (AA), catalase (CAT), superoxide dismutase (SOD), and selenium-glutathione peroxidase (Se-GPx) were measured in the livers of Ob and lean (Ln) Zucker rats before and after treatment with high-dose TOC and ascorbate. Also, survival in treated Ob rats following a lethal 90 minutes of partial in vivo warm ischemia was examined. Fatty livers of Ob rats contained significantly less GSH, TOC, and CAT, in comparison with livers of Ln rats. Immunoblotting showed significantly decreased CAT protein without changes in mRNA in fatty livers. There were no significant differences in AA, SOD, and Se-GPx between the 2 groups. Pretreatment with TOC and ascorbate over 48 hours completely corrected the decreases in GSH, TOC, and CAT. Most importantly, TOC with or without ascorbate pretreatment significantly improved survival in Ob rats following ischemia in a dosedependent manner. Fatty livers in humans and experimental animals are more prone to a variety of insults such as ischemia/reperfusion (I/ RP), endotoxin, and alcohol. Nonalcoholic steatohepatitis and its progression to cirrhosis are well-defined clinical entities. 1 Recipients of human donor livers with moderate or severe steatosis have decreased graft and patient survival. 2 Although exact figures are not available, it is believed that as many as 30% of donor livers have varying degrees of steatosis on routine microscopic examination. About 10% of donor livers are not used for transplantation because of moderate to severe steatosis, and this worsens the current shortage of livers. 2 Treatment regimens that will improve tolerance of fatty livers to the aforementioned insults are needed, and would benefit a diverse group of patients.Two rodent models of fatty liver, the genetically obese (Ob) and lipotrope-deficient diet models, are used in the laboratory to further investigate the problems associated with fatty livers. Abnormalities in sinusoidal microcirculation, 3,4 mitochondrial oxidative phosphorylation including a decrease in adenosine triphosphate production, 5,6 and dysregulation of cytokine production 7 are some of the mechanisms that have been associated with the increased injury to fatty livers in both rodents and humans. Oxidative stress has recently been postulated to be a common feature in fatty livers of diverse etiologies. 1 Lipid peroxidation products in the liver are increased in both models of rat fatty liver. 8,9 Reactive oxygen intermediates are key mediators of I/RP injury in solid organs. Thus, a 2-step oxidative injury comprised of a chronic oxidative stress before and an additional acute oxidative stress following I/RP may explain the increased injury sustained by fatty livers following both cold and warm ischemia.To...

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Section: Discussionmentioning

confidence: 51%

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

2001

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“…We used adenoviral vectors encoding dominant-negative HA-tagged Rac1 (AdN17Rac1), 2 human Cu/Zn-superoxide dismutase (SOD; AdCu/ZnSOD), 2,20,21 and ␤-galactosidase (AdLacZ). The vectors were constructed in the Gene Transfer Core Laboratory at the University of Iowa.…”

Section: In Vivo Gene Transfer Into the Ntsmentioning

confidence: 99%

Inhibition of Rac1-Derived Reactive Oxygen Species in Nucleus Tractus Solitarius Decreases Blood Pressure and Heart Rate in Stroke-Prone Spontaneously Hypertensive Rats

et al. 2007

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Abstract-Reactive oxygen species (ROS) in the brain are thought to contribute to the neuropathogenesis of hypertension by enhancing sympathetic nervous system activity. The nucleus tractus solitarius (NTS), which receives afferent input from baroreceptors, has an important role in cardiovascular regulation. reduced nicotinamide-adenine dinucleotide phosphate oxidase is thought to be a major source of ROS in the NTS. Rac1 is a small G protein and a key component of reduced nicotinamide-adenine dinucleotide phosphate oxidase. The role of Rac1-derived ROS in the NTS in cardiovascular regulation of hypertension is unknown. Therefore, we examined whether inhibition of Rac1 in the NTS decreases ROS generation, thereby reducing blood pressure in stroke-prone spontaneously hypertensive rats (SHRSPs).The basal Rac1 activity level in the NTS was greater in SHRSPs than in Wistar-Kyoto rats. Inhibition of Rac1, induced by transfecting adenovirus vectors encoding dominant-negative Rac1 into the NTS, decreased blood pressure, heart rate, and urinary norepinephrine excretion in SHRSPs but not in Wistar-Kyoto rats. Inhibition of Rac1 also reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and ROS generation. In addition, Cu/Zn-superoxide dismutase activity in the NTS of SHRSPs was decreased compared with that of Wistar-Kyoto rats, despite the increased ROS generation. Overexpression of Cu/Zn-superoxide dismutase in the NTS decreased blood pressure and heart rate in SHRSPs. These results indicate that the activation of Rac1 in the NTS generates ROS via reduced nicotinamide-adenine dinucleotide phosphate oxidase in SHRSPs, and this mechanism might be important for the neuropathogenesis of hypertension in SHRSPs. Key Words: blood pressure Ⅲ heart rate Ⅲ sympathetic nervous system Ⅲ hypertension Ⅲ brain T here is accumulating evidence that reactive oxygen species (ROS) in the cardiovascular regulatory nuclei in the brain have a crucial role in blood pressure regulation in hypertension via modulating the sympathetic nervous system. 1-5 Reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase is a major source of ROS in hypertension 6 and has a critical role in generating ROS in the brain. 2,5,7 Rac1 is a small G protein that is an important signaling molecule involved in integrating intracellular transduction pathways toward NAD(P)H oxidase activation. 2,8,9 Rac1 requires lipid modifications to migrate from the cytosol to the plasma membrane, which is a necessary step for activating the ROSgenerating NAD(P)H oxidase enzyme system. 8,9 The nucleus tractus solitarius (NTS) in the brain stem has an important role in cardiovascular regulation. 10 -16 The NTS receives afferent input from baroreceptors and chemoreceptors 12 and has reciprocal interconnections with other nuclei involved in central autonomic regulation. 17 In addition, the essential NAD(P)H oxidase subunit gp91 phox is present in somatodendritic and axonal profiles that contain angiotensin II (Ang II) subtype 1 receptors in the NTS, and Ang I...

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“…Approaches that have been used in experimental animal models of liver transplantation include antibodies to leukocyte͞ endothelial cell adhesion sites, inhibitors of Kupffer cell activation, and various antioxidant measures. The latter have included superoxide dismutase, given by gene therapy or in liposomes, various scavengers of ROS, and up-regulation of heme oxygenase-1, a heat-shock protein (9)(10)(11)(12). The effectiveness of these interventions has been variable.…”

Section: Ischemia͞reperfusion (I͞r) Injury Is a Serious Potential Thrmentioning

confidence: 99%

Bucillamine, a thiol antioxidant, prevents transplantation-associated reperfusion injury

Amersi

Nelson

Shen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Ischemia͞reperfusion (I͞R) injury is a serious potential threat to outcomes in organ transplantation and other clinical arenas inwhich there is temporary interruption of blood flow. I͞R is a frequent cause of primary failure in organ transplantation. We hypothesized that the antioxidant bucillamine, a potent sulfhydryl donor, would protect against I͞R injury in high-risk organ transplants. Because livers subjected to prolonged ischemia and very fatty livers are highly susceptible to severe I͞R injury, we studied the effect of bucillamine in three animal models of liver transplantation: two ex vivo models of isolated perfused livers, either normal or fatty rat livers, and an in vivo model of syngenic orthotopic liver transplants in rats. In all models, livers were deprived of oxygen for 24 h before either ex vivo reperfusion or transplantation. In the ex vivo models, bucillamine treatment significantly improved portal vein blood flow and bile production, preserved normal liver architecture, and significantly reduced liver enzyme release and indices of oxidative stress. Moreover, bucillamine treatment significantly increased levels of reduced glutathione in the liver and lowered levels of oxidized glutathione in both liver and blood. In rats subjected to liver transplants, bucillamine significantly enhanced survival and protected against hepatic injury. Possible mechanisms of this protection include prevention of excessive accumulation of toxic oxygen species, interruption of redox signaling in hepatocytes, and inhibition of macrophage activation. This study demonstrates the potential utility of bucillamine or other cysteine-derived thiol donors for improving outcomes in organ transplantation and other clinical settings involving I͞R injury.

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Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat

Cited by 77 publications

References 35 publications

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

Oxidative stress in fatty livers of obese Zucker rats: Rapid amelioration and improved tolerance to warm ischemia with tocopherol

Inhibition of Rac1-Derived Reactive Oxygen Species in Nucleus Tractus Solitarius Decreases Blood Pressure and Heart Rate in Stroke-Prone Spontaneously Hypertensive Rats

Bucillamine, a thiol antioxidant, prevents transplantation-associated reperfusion injury

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