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J Biol Chem. 2000 Aug 11;275(32):24583-9.

Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium. Implications for the mechanisms of aortic aneurysm and heart failure.

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Section on Cardiology, Department of Medicine, and Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1045, USA.


Cyclooxygenase-2 (COX-2) catalyzes prostaglandin synthesis from arachidonic acid and is expressed locally in aortic aneurysm and heart failure. Cellular hypoxia is also found in these conditions. We have previously shown that cox-2 is transcriptionally regulated by hypoxia in human umbilical vein endothelial cells (HUVEC) in culture via the transactivation factor NF-kappaB p65, leading to increased production of prostaglandin E(2), an inhibitor of vascular smooth muscle cell proliferation. Sp1 is a transactivation factor known to be important in the regulation of cytokine expression in association with NF-kappaB. We hypothesized that Sp1 is involved in the induction of cox-2 in hypoxic HUVEC. Electrophoretic mobility shift assays with hypoxic HUVEC nuclear protein showed that both Sp1 and the related protein Sp3 specifically bound to the cox-2 promoter. Immunoblotting demonstrated that hypoxia increased the nuclear localization of Sp1 but did not change the Sp3 content in HUVEC. Overexpression of Sp1 through transfection of HUVEC enhanced cox-2 promoter activity as measured by reporter gene expression and by the production of COX-2. The specificity of the results was confirmed by mutation of the Sp1-binding site in the cox-2 promoter construct and by reproducibility in an Sp-deficient Drosophila SL2 cell line. The regulatory role of Sp1 discovered in this work supports the concept that a mechanistic link exists between vascular cellular hypoxia and mediators of inflammation associated with aortic aneurysm and heart failure.

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