Key result
17beta-estradiol blocked iNOS synthesis and activity in control but not in diabetic rat aortic smooth muscle cells, associated with increased ERbeta expression.
Diabetes impairs the estrogenic control of iNOS in vascular smooth muscle cells, potentially due to overexpression of ERbeta, which may contribute to diabetic vascular dysfunction.
Answers are grounded in this paper and cite their sources.
May blunt estrogen-mediated vascular protection in diabetes; leaves open ERbeta as a therapeutic target in diabetic vasculopathy.
BACKGROUND: Previous reports from our group have shown that 17beta-estradiol reduces the synthesis and activity of inducible nitric oxide synthase (iNOS) in rat aortic smooth muscle cells (SMC) in response to inflammatory mediators. In this study, we investigated the effect of 17beta-estradiol on iNOS function in aortic SMC from streptozotocin-diabetic rats. METHODS AND RESULTS: Comparative analysis of NO release and of iNOS mRNA and protein content after 24-hour stimulation with a cytokine mixture revealed milder iNOS activation in diabetic than in control SMC. Furthermore, 17beta-estradiol dose-dependently blocked iNOS synthesis and activity in control but not in diabetic SMC. The defective estrogen response in diabetic SMC at 24 hours could not be attributed to reduced expression of estrogen receptors (ER). In fact, mRNA and protein levels of ERalpha and, to a greater extent, of ERbeta, were increased in diabetic compared with nondiabetic SMC. Cytokines decreased ERalpha and ERbeta expression in both groups. However, 17beta-estradiol dose-dependently restored the expression of ERalpha but further downregulated that of ERbeta, indicating a differential regulation of ER isoforms. CONCLUSIONS: Estrogenic control of iNOS was impaired in diabetic SMC. This was associated with a larger increase of ERbeta than of ERalpha protein, whereas 17beta-estradiol regulated the two isoforms in an opposite fashion. Thus, modifications in the estrogen modulation of iNOS and in the expression pattern of ER may be involved in diabetic vascular dysfunction.
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Maggi et al. (2003) studied Diabetes. 17beta-estradiol vs. Control SMC / no estradiol was evaluated on iNOS synthesis and activity (NO release, iNOS mRNA and protein content). 17beta-estradiol blocked iNOS synthesis and activity in control but not in diabetic rat aortic smooth muscle cells, associated with increased ERbeta expression.
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