title: Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.
abstract: Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Yao
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Behring
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Shao
authors.affiliation: Myocardial Biology Unit, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sverdlov
authors.affiliation: Cardiovascular Proteomics Center, Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Whelan
authors.affiliation: Myocardial Biology Unit, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Aly
authors.initials: A
authors.lastname: Elezaby
authors.affiliation: Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.affiliation: Myocardial Biology Unit, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Siwik
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
authors.affiliation: Cardiovascular Proteomics Center, Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Reiko
authors.initials: R
authors.lastname: Matsui
authors.affiliation: Myocardial Biology Unit, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
authors.affiliation: Cardiovascular Proteomics Center, Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: McComb
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000096:biosynthesis* / Q000235:genetics; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D005260:Female; D006331:Heart Diseases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D009124:Muscle Proteins; D006861:Hydrogen Peroxide; D002374:Catalase; D003545:Cysteine