| First Author | Wang C | Year | 2005 |
| Journal | Cardiovasc Res | Volume | 65 |
| Issue | 1 | Pages | 187-94 |
| PubMed ID | 15621046 | Mgi Jnum | J:134626 |
| Mgi Id | MGI:3789424 | Doi | 10.1016/j.cardiores.2004.09.026 |
| Citation | Wang C, et al. (2005) Egr-1 negatively regulates expression of the sodium-calcium exchanger-1 in cardiomyocytes in vitro and in vivo. Cardiovasc Res 65(1):187-94 |
| abstractText | 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. |
