title: Glutathione peroxidase 1-deficient mice are more susceptible to doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin (DOX)-induced cardiotoxicity is thought to be mediated by the generation of superoxide anion radicals (superoxide) from redox cycling of DOX in cardiomyocyte mitochondria. Reduction of superoxide generates H(2)O(2), which diffuses throughout the cell and potentially contributes to oxidant-mediated cardiac injury. The mitochondrial and cytosolic glutathione peroxidase 1 (Gpx1) primarily functions to eradicate H(2)O(2). In this study, we hypothesize that Gpx1 plays a pivotal role in the clearance of H(2)O(2) generated by DOX. To test this hypothesis, we compared DOX-induced cardiac dysfunction, mitochondrial injury, protein nitration, and apoptosis in Gpx1-deficient and wild type mouse hearts. The Gpx1-deficient hearts showed increased susceptibility to DOX-induced acute functional derangements than wild type hearts, including impaired contractility and diastolic properties, decreased coronary flow rate, and reduced heart rate. In addition, DOX treatment impaired the mitochondrial function of Gpx1-deficient hearts. Specifically, Gpx1-deficient hearts treated with DOX demonstrated an increased rate of NAD-linked state 4 respiration and a decline in the P/O ratio relative to wild type hearts, suggesting that DOX uncouples the electron transfer chain and oxidative phosphorylation in Gpx1-deficient hearts. Finally, apoptosis and protein nitration were significantly increased in Gpx1-deficient mouse hearts compared to wild type hearts. These studies suggest that Gpx1 plays significant roles in protecting DOX-induced mitochondrial impairment and cardiac dysfunction in the acute phase.
authors.affiliation: Cecile Cox Quillen Laboratory of Geriatric Research, James Quillen College of Medicine, East Tennessee State University, James H. Quillen Veterans Affairs Medical Center, Johnson City, TN 37614, USA.
authors.forename: Jinping
authors.initials: J
authors.lastname: Gao
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.forename: Xuwan
authors.initials: X
authors.lastname: Liu
authors.forename: Chu Chang
authors.initials: CC
authors.lastname: Chua
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Ronald
authors.initials: R
authors.lastname: Hamdy
authors.forename: Balvin H L
authors.initials: BH
authors.lastname: Chua
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009584:Nitrogen / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D004317:Doxorubicin; D005979:Glutathione Peroxidase; D009584:Nitrogen; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse