Elevated Egr-1 in Human Atherosclerotic Cells Transcriptionally Represses the Transforming Growth Factor-β Type II Receptor

Abstract

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.

Integration of the Non-genomic and Genomic Actions of Estrogen

“…Several members of the EGR family of transcription factors were identified as induced by E 2 in our array. Egr-1 is up-regulated (and important) in the response to acute and chronic vascular injury, where it may serve a protective function (34,35). E 2 mitigates the acute injury response to carotid angioplasty (36), perhaps in part through inducing Egr-1 in the EC, as shown here.…”

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

“…Atherosclerotic Tissue Samples and Immunohistochemical Staining-Slides containing thin sections of paraffin-embedded human artery tissues with or without atherosclerotic lesions were obtained from carotid endarterectomy as waste surgical specimens under Institutional Review Board-approved protocols as previously described (31,32,35). Immunohistochemical staining was conducted as follow: slides were deparaffinized and then rehydrated.…”

“…These cell lines were originally isolated from the fibrous cap of human atherosclerotic lesions, possessing characteristics of myofibroblasts and were resistant to the antiproliferative effects of transforming growth factor-␤ and the pro-apoptotic effects of Fas ligation, similar to activated, apoptosis-resistant SMCs in neointima (35,36). Although we documented that overexpression of ApoL6 induced mitochondria-and caspase 8-mediated apoptosis by release of apoptogenic factors from mitochondria and activation of caspases in various cells, including human umbilical vein endothelial cells (HUVECs) (37), the role of ApoL6 in atherosclerosis has not been explored.…”

Thematic review series: The Immune System and Atherogenesis. Cytokine regulation of macrophage functions in atherogenesis

“…Scavenger receptor class B type I (SR-BI) was originally identified as a protein that binds oxidized LDL before the realization that it is a physiologically important HDL receptor (91,92). SR-BI is expressed in macrophages and is distinct from the other receptors discussed above in that it can transfer lipid bidirectionally (8). The presence of SR-BI in macrophages has important consequences on the development of atherosclerosis, although the effect is complex, as may be expected for a receptor with this duality of function (93,94).…”

“…The original receptor for modified lipoproteins was designated a "scavenger receptor" based on its ability to mediate the endocytosis of acetylated LDL (59). There are now many proteins that have been designated as scavenger receptors that are broadly classified by gross structural characteristics in an alphabetic system (8).…”