RGD Reference Report - Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging. - Rat Genome Database

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Glutaredoxin regulates apoptosis in cardiomyocytes via NFkappaB targets Bcl-2 and Bcl-xL: implications for cardiac aging.

Authors: Gallogly, MM  Shelton, MD  Qanungo, S  Pai, HV  Starke, DW  Hoppel, CL  Lesnefsky, EJ  Mieyal, JJ 
Citation: Gallogly MM, etal., Antioxid Redox Signal. 2010 Jun 15;12(12):1339-53. doi: 10.1089/ars.2009.2791.
RGD ID: 9686063
Pubmed: PMID:19938943   (View Abstract at PubMed)
PMCID: PMC2864653   (View Article at PubMed Central)
DOI: DOI:10.1089/ars.2009.2791   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GlrxRatnegative regulation of hydrogen peroxide-mediated programmed cell death  IMP  RGD 
GlrxRatpositive regulation of non-canonical NF-kappaB signal transduction  IMP  RGD 
GlrxRatresponse to ischemia  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Glrx  (glutaredoxin)


Additional Information