Overproduction of reactive oxygen species and increasing oxidative stress have emerged as the major factors leading to mitochondrial dysfunction during myocardial ischemia and reperfusion (I/R) injury. Under normal physiology conditions, glutathione (GSH) concentration is high in the mitochondrial redox pool However, GSH is oxidized to GSSG (oxidized glutathione) upon the exposure of oxidative stress, such as the overproduction of ·O 2– and ·O2 – derived oxidants during I/R injury. Decreased GSH/GSSG ratio was found to enhance protein S-glutathiolation of complex I, which serves as a redox marker for mitochondrial dysfunction in vivo. Excess GSSG normally is recycled to GSH by mitochondrial glutathione reductase (GR2 isoform) in maintaining the basal level of complex I S-glutathiolation and redox homeostasis in mitochondria. Available evidence has indicated that protein S-glutathiolation in vitro can be induced by GSSG through the reaction of protein thiol-disulfide exchange. Thus we hypothesize that GR2 deficiency will impair mitochondrial function and subsequently heart function via enhancing S-glutathiolation of complex I. Furthermore, there is little understanding toward the role of GR2 in mitochondrial dysfunction, and the mechanism of GR2-mediated S-glutathiolation of Complex I. We first performed the study in the heart of a post-ischemic rat model to evaluate the alteration in GR2 activity after myocardial infarction. Rats received intraperitoneal administration of 3-bischoloroethyl-1-nitrosourea(BCNU), a GR2 inhibitor. We observed systolic dysfunction, decreased respiratory control ratio, and increased ·O2– generation under the condition of state 3 respiration after BCNU treatment. We also found decreased GSH/GSSG ratio, increased redox activity and increased Complex I S-glutathiolation. These data suggest that mitochondrial GR deficiency and mitochondrial oxidative stress and associated redox modification are the molecular mechanisms of BCNU induced systolic dysfunction. The above studies were further evaluated using the animal model of cardiac-specific SOD2 transgenic mice. The overexpression of SOD2 reversed the BCNU-induced GR2 inhibition and mitochondrial impairment.
|Commitee:||Bratz, Ian, Carroll, Richard|
|School:||Kent State University|
|School Location:||United States -- Ohio|
|Source:||MAI 52/06M(E), Masters Abstracts International|
|Subjects:||Pharmacology, Biochemistry, Biomedical engineering|
|Keywords:||Glutathione, Mitochondrial dysfunction, Myocardial ischemia, Oxidative stress, Reactive oxygen species|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be