Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo
Identifieur interne : 000D14 ( Main/Merge ); précédent : 000D13; suivant : 000D15Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo
Auteurs : Filio Billia [Canada] ; Ludger Hauck [Canada] ; Daniela Grothe [Canada] ; Filip Konecny [Canada] ; Vivek Rao [Canada] ; Raymond H. Kim [Canada] ; Tak W. Mak [Canada]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2013.
English descriptors
- KwdEn :
- Angiotensin II (metabolism), Animals, Antioxidants (metabolism), Apoptosis, Down-Regulation, Echocardiography, Female, Genetic Predisposition to Disease, Humans, Intracellular Signaling Peptides and Proteins (physiology), Male, Mice, Mice, Knockout, Microscopy, Fluorescence, Myocardium (metabolism), Myocytes, Cardiac (cytology), Oncogene Proteins (physiology), Oxidative Stress, Peroxiredoxins, Protein Deglycase DJ-1, Reactive Oxygen Species.
- MESH :
- chemical , metabolism : Angiotensin II, Antioxidants.
- chemical , physiology : Intracellular Signaling Peptides and Proteins, Oncogene Proteins.
- cytology : Myocytes, Cardiac.
- metabolism : Myocardium.
- Animals, Apoptosis, Down-Regulation, Echocardiography, Female, Genetic Predisposition to Disease, Humans, Male, Mice, Mice, Knockout, Microscopy, Fluorescence, Oxidative Stress, Peroxiredoxins, Protein Deglycase DJ-1, Reactive Oxygen Species.
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.
Url:
DOI: 10.1073/pnas.1303444110
PubMed: 23530187
PubMed Central: 3625258
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PMC:3625258Le document en format XML
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Mak</name><affiliation wicri:level="1"><nlm:aff id="aff1">Campbell Family Cancer Research Institute,<institution>Princess Margaret Hospital</institution>, Toronto, ON,<country>Canada</country> M5G 2M9;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Angiotensin II (metabolism)</term><term>Animals</term><term>Antioxidants (metabolism)</term><term>Apoptosis</term><term>Down-Regulation</term><term>Echocardiography</term><term>Female</term><term>Genetic Predisposition to Disease</term><term>Humans</term><term>Intracellular Signaling Peptides and Proteins (physiology)</term><term>Male</term><term>Mice</term><term>Mice, Knockout</term><term>Microscopy, Fluorescence</term><term>Myocardium (metabolism)</term><term>Myocytes, Cardiac (cytology)</term><term>Oncogene Proteins (physiology)</term><term>Oxidative Stress</term><term>Peroxiredoxins</term><term>Protein Deglycase DJ-1</term><term>Reactive Oxygen Species</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Angiotensin II</term><term>Antioxidants</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Intracellular Signaling Peptides and Proteins</term><term>Oncogene Proteins</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Myocytes, Cardiac</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Myocardium</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Apoptosis</term><term>Down-Regulation</term><term>Echocardiography</term><term>Female</term><term>Genetic Predisposition to Disease</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Knockout</term><term>Microscopy, Fluorescence</term><term>Oxidative Stress</term><term>Peroxiredoxins</term><term>Protein Deglycase DJ-1</term><term>Reactive Oxygen Species</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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