Copyright © 2004, European Society of Cardiology
Egr-1 negatively regulates expression of the sodium–calcium exchanger-1 in cardiomyocytes in vitro and in vivo
aLady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 chemin Côte Ste Catherine, Montréal, Québec, Canada, H3T 1E2.
bDivision of Experimental Medicine, Department of Medicine, McGill University, Montreal, Canada
cThe Bank of Montréal Research Center for the Study of Heart Disease in Women, Sir Mortimer B. Davis-Jewish General Hospital, Canada
* Corresponding author. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 chemin Côte Ste Catherine, Montréal, Québec, Canada, H3T 1E2. Tel.: +1 514 340 8222x4295; fax: +1 514 340 7502. Email address: lorraine.chalifour{at}mcgill.ca
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 naïve –/– 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.
KEYWORDS Adrenergic agonist; Heart failure; Gene expression; Remodelling; Sodium calcium exchanger
Time for primary review 26 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Kasneci, N. M. Kemeny-Suss, S. V. Komarova, and L. E. Chalifour Egr-1 negatively regulates calsequestrin expression and calcium dynamics in ventricular cells Cardiovasc Res, March 1, 2009; 81(4): 695 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Holaska Emerin and the Nuclear Lamina in Muscle and Cardiac Disease Circ. Res., July 3, 2008; 103(1): 16 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dunnick, P. Blackshear, G. Kissling, M. Cunningham, J. Parker, and A. Nyska Critical Pathways in Heart Function: Bis(2-chloroethoxy)methane-Induced Heart Gene Transcript Change in F344 Rats Toxicol Pathol, June 1, 2006; 34(4): 348 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. James, A.-M. Conway, and B. J. Morris Regulation of the Neuronal Proteasome by Zif268 (Egr1) J. Neurosci., February 1, 2006; 26(5): 1624 - 1634. [Abstract] [Full Text] [PDF]
|
|