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You are here: Contents > 2004 > Volume 13 Number 6 November 2004 > AORTIC VALVE DISEASE > Transcription Factor Egr-1 in Calcific Aortic Valve Disease

Transcription Factor Egr-1 in Calcific Aortic Valve Disease

Marjan Ghazvini-Boroujerdi, Jocelyn Clark, Navneet Narula, Elizabeth Palmatory, Jeanne M. Connolly, Suzanne DeFelice, Jie Xu, Bo Jian, Senator Hazelwood, Robert J. Levy
Cardiology Research Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA, Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA

Background and aim of the study: Previous immunohistochemistry studies have shown that the transcription factor, Egr-1, is increased in human atherosclerotic lesions but is absent from the normal adjacent aortic wall. The hypothesis was investigated that Egr-1 is also increased in calcified heart valve cusps because of the unique presence in these tissues of proteins known to be regulated by Egr-1, such as tenascin C (TN-C).
Methods: Non-calcified and calcified human aortic valves were obtained at autopsy or from cardiac surgery. Egr-1 immunohistochemical studies were performed. The effects of Egr-1 on cellular proliferation and on mechanisms of calcification were also investigated using sheep aortic valve interstitial cell (SAVIC) cultures. Signal transduction pathways involving Egr-1 were studied with specific inhibitors.
Results: Immunohistochemical studies revealed that calcific aortic stenosis cusps contained a significantly higher level of Egr-1 in the spindle-shaped interstitial cells of calcified human aortic valves, but not white blood cells. By comparison, Egr-1 was detected at very low levels in the interstitial cells of non-calcified human aortic valve cusps.

SAVIC cultivated on denatured versus native collagen substrates demonstrated a marked increase in Egr-1 levels (by Western blotting), and an absence of calcification in these cultures, compared to SAVIC grown on native collagen which calcified severely with little Egr-1 expression. Parallel increases in TN-C and osteopontin (OPN), both of which are proteins associated with heart valve calcification, were observed (by Western blotting) in SAVIC grown on denatured collagen. Furthermore, a protein kinase-C (PKC) inhibitor blocked the up-regulation of Egr-1 and TN-C, implicating PKC-dependent signaling control of Egr-1 and TN-C up-regulation.
Conclusion: Egr-1 is up-regulated in human calcific aortic stenosis cusps compared to non-calcified normal cusps. Egr-1 up-regulation involves a PKC-dependent signaling pathway. TN-C and OPN appear to be co-regulated with Egr-1. Furthermore, in SAVIC cultures on denatured collagen, Egr-1 up-regulation was associated with inhibition of calcification. Taken together, these results suggest that complex Egr-1 mechanisms may be operative in calcific aortic stenosis.
The Journal of Heart Valve Disease 2004;13:894-903

Transcription Factor Egr-1 in Calcific Aortic Valve Disease

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