| Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging. | |
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MedLine Citation:
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PMID: 19938943 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cardiomyocyte apoptosis is a well-established contributor to irreversible injury following myocardial infarction (MI). Increased cardiomyocyte apoptosis is associated also with aging in animal models, exacerbated by MI; however, mechanisms for this increased sensitivity to oxidative stress are unknown. Protein mixed-disulfide formation with glutathione (protein glutathionylation) is known to change the function of intermediates that regulate apoptosis. Since glutaredoxin (Grx) specifically catalyzes protein deglutathionylation, we examined its status with aging and its influence on regulation of apoptosis. Grx1 content and activity are decreased by approximately 40% in elderly (24-mo) Fischer 344 rat hearts compared to adult (6-mo) controls. A similar extent of Grx1 knockdown in H9c2 cardiomyocytes led to increased apoptosis, decreased NFkappaB-dependent transcriptional activity, and decreased production (mRNA and protein) of anti-apoptotic NFkappaB target genes, Bcl-2 and Bcl-xL. Knockdown of Bcl-2 and/or Bcl-xL in wild-type H9c2 cells to the same extent ( approximately 50%) as observed in Grx1-knockdown cells increased baseline apoptosis; and knockdown of Bcl-xL, but not Bcl-2, also increased oxidant-induced apoptosis analogous to Grx1-knockdown cells. Natural Grx1-deficient cardiomyocytes isolated from elderly rats also displayed diminished NFkappaB activity and Bcl-xL content. Taken together, these data indicate diminution of Grx1 in elderly animals contributes to increased apoptotic susceptibility via regulation of NFkappaB function. |
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Authors:
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Molly M Gallogly; Melissa D Shelton; Suparna Qanungo; Harish V Pai; David W Starke; Charles L Hoppel; Edward J Lesnefsky; John J Mieyal |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: 12 ISSN: 1557-7716 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-06 Completed Date: 2010-07-27 Revised Date: 2012-05-23 |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: United States |
Other Details:
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Languages: eng Pagination: 1339-53 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4965, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aging
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metabolism* Animals Apoptosis / drug effects, physiology* Cells, Cultured / cytology, drug effects, metabolism Gene Expression Regulation / drug effects, physiology Gene Knockdown Techniques Genes, bcl-2 Glutaredoxins / antagonists & inhibitors, genetics, physiology* Hydrogen Peroxide / pharmacology Male Myocardium / metabolism* Myocytes, Cardiac / cytology*, drug effects, metabolism NF-kappa B / antagonists & inhibitors, physiology* Oxidation-Reduction Proto-Oncogene Proteins c-bcl-2 / biosynthesis, genetics, physiology* RNA, Messenger / biosynthesis RNA, Small Interfering / pharmacology Rats Rats, Inbred F344 bcl-X Protein / biosynthesis, genetics, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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F30 AG029687A/AG/NIA NIH HHS; P01 AG15885/AG/NIA NIH HHS; R01 AG024413/AG/NIA NIH HHS; T32 EY007157/EY/NEI NIH HHS; T32 EY07157/EY/NEI NIH HHS; T32 GM008803/GM/NIGMS NIH HHS; T32 GM07250/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bcl2l1 protein, rat; 0/Glutaredoxins; 0/NF-kappa B; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/bcl-X Protein; 7722-84-1/Hydrogen Peroxide |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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