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

Summary

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-β, IL-1βTNF-α, VEGF, thrombin). The genes selected accordingly were: cytochrome P450 1B1, diaphorase and the transcription factor lung Krüppel-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 TR3ΔTA 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 TR3ΔTA 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 TR3ΔTA and TR3, respectively, inhibit and promote the synthesis of the cyclin-dependent kinase inhibitor p27^Kip1 in SMC.

Part of this work was presented at the 16th Congress of the International Society on Fibrinolysis and Proteolysis, Munich, Germany, September 2002.

Keywords

Atherosclerosis - DNA micro-array - lung Krüppel-like factor - TR3 - p27^Kip1

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