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Thromb Haemost. 2003 Mar;89(3):522-9.

Focusing on transcription factor families in atherogenesis: the function of LKLF and TR3.

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  • 1Academic Medical Center, Department of Biochemistry (K1-159), Meibergdreef 15, 1105 Amsterdam, The Netherlands.

Abstract

In this overview, two separate studies are discussed that emerged from a "discovery-driven" approach to identify genes that play an essential role in atherogenesis. First, by a combination of DNA micro-array and one-way linkage hierachical clustering, we selected genes that are induced in endothelial cells (EC) by prolonged steady- or pulsatile laminar flow, but of which expression is not affected by inflammatory and mitogenic agents (TGF-beta, IL-1betaTNF-alpha,VEGF, thrombin). The genes selected accordingly were: cytochrome P450 1B1, diaphorase and the transcription factor lung Kr├╝ppel-like factor (LKLF) of which only the latter is truly EC specific. LKLF meets the criteria of an anti-atherosclerotic gene, mainly since expression is restricted to areas subjected to laminar flow as shown by in situ hybridization with anatomically well-defined specimens. Second, neointimal (but not medial) smooth muscle cells (SMC) specifically synthesize the NGFI-B subfamily (TR3, MINOR,NOT) of the nuclear hormone superfamily of transcription factors. Again, evidence is presented, indicating that these proteins serve an anti-atherosclerotic function. Notably, transgenic mice, expressing either TR3 or a dominant-negative mutant TR3DeltaTA in arterial SMC, were subjected to carotid artery ligation to induce SMC proliferation. Lesions in TR3-overexpressing transgenic mice were 5-fold smaller than isogenic wild-type mice, while mice overexpressing the TR3DeltaTA mutant had a 3-fold larger lesion. It is proposed that (down-stream products of) TR3 inhibit the cell cycle, since adenovirus-mediated expression of TR3DeltaTA and TR3, respectively, inhibit and promote the synthesis of the cyclin-dependent kinase inhibitor p27(Kip1) in SMC.

PMID:
12624637
[PubMed - indexed for MEDLINE]
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