Document Detail


Egr-1 negatively regulates expression of the sodium-calcium exchanger-1 in cardiomyocytes in vitro and in vivo.
MedLine Citation:
PMID:  15621046     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Increased expression of the transcription factor early growth response gene-1 (Egr-1) accompanies catecholamine infusion. Catecholamine-treated, Egr-1-deficient (-/-) mice show exacerbated cardiac damage when compared to similarly treated wild-type (+/+) mice, suggesting that Egr-1 reduces heart damage. We sought to identify Egr-1-mediated cardiac sparing genes. METHODS: Microarray analyses identified increased sodium calcium exchanger-1 (NCX1) expression in catecholamine-treated -/- mice. Immunoblots assessed NCX1 expression in +/+, -/-, and transgenic mice overexpressing Egr-1 in heart and cardiac differentiated H9c2 cells harboring wild-type Egr-1 (wtEgr-1) or NAB-binding ablating mutations. Chromatin immunoprecipitation (ChIP) used anti-Egr-1 antibody coupled to amplification of purified Egr-1/associated DNA. RESULTS: Immunoblots revealed a two- to threefold increase in NCX1 in catecholamine-stimulated and naive -/- versus +/+ mice. In contrast, transgenic mice overexpressing Egr-1 in heart had 30% of normal NCX1 protein. Thus, the in vivo data indicate that Egr-1 negatively controls NCX1 expression. In vitro cardiac differentiated H9c2 cells overexpressing wtEgr-1 also showed 30% NCX1 expression. However, cells overexpressing NAB-ablating Egr-1 mutations showed four- to fivefold increased NCX1 expression. NCX1 promoter DNA was specifically amplified from Egr-1/associated DNA. Thus, the in vitro results indicate that Egr-1/NAB interactions are critical for NCX1 repression at the NCX1 promoter. CONCLUSIONS: NCX1 is responsible for calcium exit from cardiomyocytes, and continued overexpression is thought to be detrimental. We propose that one way Egr-1 action is cardiac sparing is by promoting a reduction in NCX1 expression.
Authors:
Chunlei Wang; Stevan Dostanic; Nicolas Servant; Lorraine E Chalifour
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular research     Volume:  65     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-28     Completed Date:  2005-03-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  187-94     Citation Subset:  IM    
Affiliation:
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 chemin Côte Ste Catherine, Montréal, Québec, Canada H3T 1E2.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
Cells, Cultured
DNA-Binding Proteins / genetics,  metabolism*
Dobutamine / pharmacology
Early Growth Response Protein 1
Immediate-Early Proteins / genetics,  metabolism*
Infusion Pumps, Implantable
Isoproterenol / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocytes, Cardiac / drug effects,  metabolism*
Oligonucleotide Array Sequence Analysis
Orciprenaline / pharmacology
Phenylephrine / pharmacology
Propranolol / pharmacology
Sodium / metabolism
Sodium-Calcium Exchanger / metabolism*
Stimulation, Chemical
Transcription Factors / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Early Growth Response Protein 1; 0/Egr1 protein, mouse; 0/Immediate-Early Proteins; 0/Sodium-Calcium Exchanger; 0/Transcription Factors; 0/sodium-calcium exchanger 1; 34368-04-2/Dobutamine; 525-66-6/Propranolol; 586-06-1/Orciprenaline; 59-42-7/Phenylephrine; 7440-23-5/Sodium; 7440-70-2/Calcium; 7683-59-2/Isoproterenol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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