title: Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo.
abstract: Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the ability of an organism to eliminate these toxic intermediates. Although the Parkinson-susceptibility gene, Parkinson protein 7/DJ-1 (DJ-1), has been linked to the regulation of oxidative stress, the exact mechanism by which this occurs and its in vivo relevance have remained elusive. In the heart, oxidative stress is a major contributor to the development of heart failure (HF). Therefore, we hypothesized that DJ-1 inhibits the pathological consequences of ROS production in the heart, the organ with the highest oxidative burden. We report that DJ-1 is highly expressed in normal heart tissue but is markedly reduced in end-stage human HF. DJ-1-deficient mice subjected to oxidative stress by transaortic banding exhibited exaggerated cardiac hypertrophy and susceptibility to developing HF. This was accompanied by a Trp53 (p53)-dependent decrease in capillary density, an excessive oxidation of DNA, and increased cardiomyocyte apoptosis, key events in the development of HF. Impaired mitochondrial biogenesis and progressive respiratory chain deficiency were also evident in cardiomyocytes lacking DJ-1. Our results provide compelling in vivo evidence that DJ-1 is a unique and nonredundant antioxidant that functions independent of other antioxidative pathways in the cellular defense against ROS.
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9.
authors.forename: Filio
authors.initials: F
authors.lastname: Billia
authors.forename: Ludger
authors.initials: L
authors.lastname: Hauck
authors.forename: Daniela
authors.initials: D
authors.lastname: Grothe
authors.forename: Filip
authors.initials: F
authors.lastname: Konecny
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Kim
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D015536:Down-Regulation; D004452:Echocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D015513:Oncogene Proteins / Q000502:physiology*; D018384:Oxidative Stress; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1