Redox modulation of the liver with chronic antioxidant enzyme mimetic treatment prevents age-related oxidative damage associated with environmental stress.
A reduction in stress tolerance is a hallmark of the aging process, and the lowered functional capacity observed in aged organisms is associated with an increased rate of oxidative stress and a greater susceptibility of aged tissues to oxidative injury. In this report, we show that chronic systemic administration of a superoxide dismutase (SOD)/catalase mimetic (EUK-189), delivered over a 1 month period via osmotic pump, prevents heat stress-induced liver injury by dramatically decreasing oxidative damage in aged animals. Widespread liver injury was present in old but not young vehicle-treated rats in response to a 2 day heating protocol. However, SOD/catalase mimetic treatment markedly decreased the hyperthermia-induced liver injury associated in old animals. The reversal of damage with EUK-189 was associated with an improvement in intracellular redox status and a striking reduction in hepatocellular lipid peroxidation. EUK-189 treatment also blocked the activation of activator protein-1 (AP-1), which is a redox-sensitive early response transcription factor involved in the regulation of cellular stress responses. These results demonstrate that oxidative stress plays a unique role in age-related hyperthermic injury and suggest that therapeutic strategies aimed at improving redox potential, such as chronic SOD/catalase mimetic treatment, can prevent the oxidative-mediated damage associated with environmental stress.
Zhang
Hannah J
HJ
Integrative Physiology Laboratory, Department of Exercise Science, University of Iowa, Iowa City, IA 52242, USA.
Doctrow
Susan R
SR
Xu
Linjing
L
Oberley
Larry W
LW
Beecher
Benjamin
B
Morrison
Joanna
J
Oberley
Terry D
TD
Kregel
Kevin C
KC
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004777:Environment; D005978:Glutathione / Q000378:metabolism; D006358:Hot Temperature; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000975:Antioxidants; C436526:EUK-189; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; D018808:Transcription Factor AP-1; D004247:DNA; D002374:Catalase; D005978:Glutathione