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CONTEXT: The decreased incidence of cardiovascular disease in premenopausal women has been attributed, at least partially, to protective effects of estrogens. However, premenopausal women with diabetes mellitus are no longer selectively protected. High-glucose (HG) conditions have previously been shown to abolish the antimitogenic effects of 17β-estradiol (E2) in vascular smooth muscle cells (VSMCs). OBJECTIVE: Because E2mediates its action via different estrogen receptor (ER) subtypes, we hypothesized that different subtypes may have different, if not opposing, effects on HG-induced VSMC proliferation. METHODS: and Results: Treatment of human aortic VSMCs isolated from premenopausal women with the selective ER agonist, 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol, but not with E2, the selective ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, or the selective G protein-coupled ER agonist G-1 completely prevented increased HG-induced VSMC proliferation. Under these conditions, ER activation selectively prevented increased hydrogen peroxide (H2O2) and total intracellular reactive oxygen species (ROS) production, caused up-regulation of manganese superoxide dismutase protein and activity, and inhibited prolonged ERK phosphorylation. The latter was mediated by ROS, and ROS inhibition reversed HG-induced ERK-dependent VSMC proliferation. The selective coactivation of ERβ reversed the antimitogenic and antioxidative effects of ER as well as the up-regulation of manganese superoxide dismutase protein expression. CONCLUSION: Selective activation of ER is required for reducing oxidative stress and the consequent hyperproliferation of VSMCs under HG. Our results may further suggest that ER activation inhibits HG-induced proliferation by down-regulating ROS-mediated ERK activation and may explain why antimitogenic effects of E2are abolished under HG. Pharmacological activation of ER may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes.

This study investigated whether intrarenal endothelin-1(ET-1) contributes to sodium excretion in aged rats. Metabolic function studies were performed in male Wistar rats (3 and 24 months) treated with placebo or the orally active ETAreceptor antagonist darusentan (20 mgkgd) for 4 weeks. Mean arterial pressure was measured using an intra-arterial catheter. Electrolytes, aldosterone levels, renin activity, and angiotensin converting enzyme activity were determined in plasma, and mRNA expression of epithelial sodium channel (ENaC) and Na, K-ATPase subunits was measured in the renal cortex and medulla. Aging was associated with a marked decrease in urinary excretion of sodium, chloride, and potassium (all P<0.001) as well as renin activity (P<0.05), but had no significant effect on gene expression of ENaC or Na, K-ATPase subunits. In aged rats, darusentan treatment increased ion excretion (P<0.05), reduced cortical gene expression of αENaC and α1-Na, K-ATPase (both P<0.05), and increased plasma aldosterone levels (P<0.01). These data demonstrate a decrease of sodium and potassium excretion in aged rats, changes that are partly sensitive to ETAreceptor blockade. Treatment with darusentan also reduced cortical expression of αENaC and α1-Na, K-ATPase and increased plasma aldosterone levels independently of blood pressure, electrolytes, renin activity, or angiotensin converting enzyme activity. These findings may provide new pathogenetic links between aging and sodium sensitivity.

In the aorta of prediabetic non-obese diabetic mice, a model of human type 1 diabetes, we investigated gene expression of the endothelin receptors and contractility to big endothelin-1 and endothelin-1 at the ages of 10 and 16 weeks. A subgroup of 10- week-old animals was treated with the endothelin ETAreceptor antagonist LU461314 (30 mg/kg per day for 6 weeks). Blood glucose levels were normal in all animals. Real-time polymerase chain reaction analysis revealed that vascular ETBreceptor expression was higher in 10-week-old non-obese diabetic (NOD) mice compared with controls. In 16-week-old NOD mice, but not in control mice, ETBreceptor mRNA was twofold lower (P< 0.05 vs 10-week-old NOD mice). In all groups ETAreceptor expression was unaffected by age or treatment. Contractions to big endothelin-1 and endothelin-1 were lower in 10-week-old NOD mice compared with controls. Treatment with LU461314 increased ETBreceptor expression in 16-week-old NOD mice, but had no effect on vascular contractility. These data indicate that dysregulation of ETBreceptor expression and a decreased contractile response to big endothelin-1 and endothelin-1 are present in the prediabetic state of a model of human type 1 diabetes. These alterations occur independent of glucose levels. Furthermore, ETAreceptor blockade is effective in increasing ETBreceptor gene expression, suggesting a potential role for endothelin ETAantagonists in the treatment of type 1 diabetes.