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Atherosclerotic lesions may progress due to a "failure to die" by vascular repair cells. Egr-1, a zinc finger transcription factor, is elevated more than 5-fold in human carotid lesions relative to the adjacent tunica media. Lesion cells in vitro also express 2-3-fold higher Egr-1 mRNA and protein levels but express much lower levels of the transforming growth factor-␤ (TGF-␤) Type II receptor (T␤R-2) and are functionally resistant to the antiproliferative effects of TGF-␤. Lesion cells fail to express a T␤R-2 promoter/chloramphenicol acetyltransferase (CAT) construct but overexpress an Egr-1-inducible platelet-derived growth factor-A promoter/CAT construct. Transfection of Egr-1 cDNA represses T␤R-2/CAT constructs but induces PDGF-A/CAT. Egr-1 transfection reduces the levels of T␤R-2 and confers resistance to the antiproliferative effect of TGF-␤1. Egr-1 can interact directly with both the ؊143 Sp1 site and the positive regulatory element 2 (PRE2) (ERT/ets) region of the T␤R-2 promoter. Thus, although activating a family of stress-responsive genes, Egr-1 also transcriptionally represses one of the major inhibitory pathways that restrains vascular repair.

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