Received for publication July 28, 2006.
Revised October 22, 2006.
Accepted for publication October 31, 2006.

17-Estradiol Antagonizes the Down-Regulation of Endothelial Nitric-Oxide Synthase and GTP Cyclohydrolase by High Glucose: Relevance to Postmenopausal Diabetic Cardiovascular Disease

Abstract

In postmenopausal women, the risk of diabetic cardiovascular disease drastically increases compared to that of men or premenopausal women. However, the mechanism for this phenomenon has not yet been clarified. We hypothesized that the beneficial effects of estrogen on endothelial function may be relevant to the protection against hyperglycemia-induced vascular derangements. Bovine aortic endothelial cells were incubated for 72 h in the presence and absence of the physiological concentration of 17-estradiol (17-E2) under normal and high glucose conditions. The presence of 17-E2 significantly counteracted the reduction in basal NO production under high glucose conditions. This finding was associated with the recovery of eNOS protein expression, BH4 level, and activity and gene expression of GTP cyclohydrolase I (GTPCH-I), a rate-limiting enzyme for BH4 synthesis. Both gene transfer of estrogen receptor (ER) using adenovirus and treatment with the protein kinase C inhibitor bisindolylmaleimide I significantly enhanced the effects of 17-E2 treatment under high glucose conditions, while these effects were completely abolished by the estrogen receptor antagonist ICI 182,780. Transfection of small interfering RNA targeting eNOS resulted in a marked reduction in GTPCH-I mRNA under both normal and high glucose conditions, but this reduction was strongly reversed by 17-E2. These results suggest that activation of ER with 17-E2 can counteract high glucose-induced down-regulation of eNOS and GTPCH-I in endothelial cells. Therefore, estrogen deficiency may result in an exaggeration of hyperglycemia-induced endothelial dysfunction, leading to the development of cardiovascular disease in postmenopausal diabetic women.

Key words: GTP Cyclohydrolase, diabetes mellitus, estrogen, nitiric oxide synthase, nitric oxide, reactive oxygen species

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