MULTIPLE CIS-ELEMENTS MEDIATE SHEAR STRESS-INDUCED GENE-EXPRESSION

Fluid shear stress activates the expression of immediate early (IE) ge nes in vascular endothelial cells. The transcriptional regulation can be mediated through the shear stress-sensitive cis-acting elements at the 5' promoter regions of various IE genes such as the monocyte chemo tactic protein-1 (MCP-1) gene. We linked wild-type and mutated MCP-1 p romoters to the reporter gene luciferase and used such constructs to i nvestigate the role of the phorbol ester TPA responsive element (TRE) in the shear-induced MCP-1 gene expression in vascular endothelial cel ls. Functional analysis showed that TGACTCC (a divergent TRE) located at nt - 54 to - 60 is necessary for shear-inducibility in bovine aorti c endothelial cells (BAEC). The induction of the wild-type MCP-1 promo ter construct by shear stress was attenuated by pretreating the cells with 1 mu M dexamethasone or 1 mu M retinoic acid 12 h before the shea r stress experiments. The induction by shear stress reduced from 13-fo ld in the untreated cells to 7- and 3-folds in the dexamethasone- and retinoic acid-treated cells, respectively. These results demonstrate t hat the glucocorticoid receptor and retinoic acid receptor may interfe re with the shear stress-activated AP-1/TRE. The reporter activity of HIV(LTR), which is a plasmid construct of the long terminal repeats of the human immunodeficiency virus and contains a kappa B enhancer elem ent, was also activated by shear stress. The results of our investigat ions indicate that the shear stress-induced IE gene expression can be mediated through multiple cis-elements.