All-trans Retinoic Acid Alleviates Hepatic Ischemia/Reperfusion Injury by Enhancing Manganese Superoxide Dismutase in Rats

Background Heat shock protein 72 (HSP72) is known to provide myocardial protection against ischemia-reperfusion injury by its chaperoning function. Target molecules of this effect are presumed to include not only structural proteins but also other self-preservation proteins. The details, however, remain unknown. Manganese superoxide dismutase (Mn-SOD) is an enzyme that preserves mitochondria, a key organelle for cellular respiration, from reperfusion injury and limits mitochondria-related apoptosis. We hypothesized that Mn-SOD would play a role in HSP72-mediated cardioprotection. Methods and Results Rat hearts were transfected with human HSP72 by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, resulting in global myocardial overexpression of HSP72. After ischemia-reperfusion injury, cardiac function (left ventricular systolic pressure, maximum dP/dt, minimum dP/dt, and coronary flow) was improved in the HSP72-transfected hearts compared with control-transfected ones, corresponding with less leakage of creatine kinase and mitochondrial aspartate aminotransferase. Postischemic Mn-SOD content and activity in the HSP72-transfected hearts were enhanced in comparison with the controls (content: 96.9±4.1 versus 85.5±2.5% to the preischemic level, P =0.038; activity: 93.9±2.2 versus 82.2±3.7%, P =0.022), associated with improved mitochondrial respiratory function (postischemic percent respiratory control index; NAD + -linked: 81.3±3.8 versus 18.5±4.4%; FAD-linked: 71.8±5.5 versus 20.7±5.3%, P <0.001). In addition, incidence of postischemic cardiomyocyte apoptosis was attenuated in the HSP72-transfected hearts (4.0±1.1 versus 10.3±3.3%, P =0.036), correlating with an increased Bcl-2 level and reduced up-regulation of caspase-3. Conclusions These data suggest that the enhanced Mn-SOD activity during ischemia-reperfusion injury, which is associated with mitochondrial protection and apoptosis reduction, is a possible mechanism of HSP72-induced cardioprotection.

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Exercise Provides Direct Biphasic Cardioprotection via Manganese Superoxide Dismutase Activation

Journal of Experimental Medicine ◽

10.1084/jem.189.11.1699 ◽

1999 ◽

Vol 189 (11) ◽

pp. 1699-1706 ◽

Cited By ~ 229

Author(s):

Nobushige Yamashita ◽

Shiro Hoshida ◽

Kinya Otsu ◽

Michio Asahi ◽

Tsunehiko Kuzuya ◽

...

Keyword(s):

Superoxide Dismutase ◽

Neutralizing Antibodies ◽

Time Course ◽

Manganese Superoxide Dismutase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Sod Activity ◽

Manganese Superoxide ◽

Tnf Α ◽

Exercise Induced

Epidemiologic investigations have shown that exercise reduces morbidity and mortality from coronary artery disease. In this study, using a rat model, we attempted to determine whether exercise can reduce ischemic injury to the heart and elucidate a mechanism for the cardioprotective effect of exercise. Results showed that exercise significantly reduced the magnitude of a myocardial infarction in biphasic manner. The time course for cardioprotection resembled that of the change in manganese superoxide dismutase (Mn-SOD) activity. The administration of the antisense oligodeoxyribonucleotide to Mn-SOD abolished the expected decrease in infarct size. We showed that the level of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) increased after exercise. The simultaneous administration of the neutralizing antibodies to the cytokines abolished the exercise-induced cardioprotection and the activation of Mn-SOD. Furthermore, TNF-α can mimic the biphasic pattern of cardioprotection and activation of Mn-SOD. An antioxidant completely abolished cardioprotection and the activation of Mn-SOD by exercise or the injection of TNF-α as well as exercise-induced increase in TNF-α and IL-1β. The production of reactive oxygen species and endogenous TNF-α and IL-1β induced by exercise leads to the activation of Mn-SOD, which plays major roles in the acquisition of biphasic cardioprotection against ischemia/reperfusion injury in rats.

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Role of reduced manganese superoxide dismutase in ischemia-reperfusion injury: a possible trigger for autophagy and mitochondrial biogenesis?

AJP Renal Physiology ◽

10.1152/ajprenal.00435.2012 ◽

2013 ◽

Vol 304 (3) ◽

pp. F257-F267 ◽

Cited By ~ 27

Author(s):

Nirmala Parajuli ◽

Lee Ann MacMillan-Crow

Keyword(s):

Oxidative Stress ◽

Superoxide Dismutase ◽

Renal Function ◽

Mitochondrial Biogenesis ◽

Renal Damage ◽

Manganese Superoxide Dismutase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Manganese Superoxide ◽

Oxidant Production

Excessive generation of superoxide and mitochondrial dysfunction has been described as being important events during ischemia-reperfusion (I/R) injury. Our laboratory has demonstrated that manganese superoxide dismutase (MnSOD), a major mitochondrial antioxidant that eliminates superoxide, is inactivated during renal transplantation and renal I/R and precedes development of renal failure. We hypothesized that MnSOD knockdown in the kidney augments renal damage during renal I/R. Using newly characterized kidney-specific MnSOD knockout (KO) mice the extent of renal damage and oxidant production after I/R was evaluated. These KO mice (without I/R) exhibited low expression and activity of MnSOD in the distal nephrons, had altered renal morphology, increased oxidant production, but surprisingly showed no alteration in renal function. After I/R the MnSOD KO mice showed similar levels of injury to the distal nephrons when compared with wild-type mice. Moreover, renal function, MnSOD activity, and tubular cell death were not significantly altered between the two genotypes after I/R. Interestingly, MnSOD KO alone increased autophagosome formation, mitochondrial biogenesis, and DNA replication/repair within the distal nephrons. These findings suggest that the chronic oxidative stress as a result of MnSOD knockdown induced multiple coordinated cell survival signals including autophagy and mitochondrial biogenesis, which protected the kidney against the acute oxidative stress following I/R.

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