RT Journal Article
SR Electronic
T1 Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 174
OP 182
DO 10.1124/jpet.108.143511
VO 328
IS 1
A1 Andrea Cignarella
A1 Chiara Bolego
A1 Valeria Pelosi
A1 Clara Meda
A1 Andrée Krust
A1 Christian Pinna
A1 Rosa Maria Gaion
A1 Elisabetta Vegeto
A1 Adriana Maggi
YR 2009
UL http://jpet.aspetjournals.org/content/328/1/174.abstract
AB Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ERα and ERβ-selective agonists 4,4′,4′′-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ERα attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17β-estradiol to aortic tissues from ERβ- but not ERα-knockout mice. These findings suggest a possible role for ERα-selective ligands in reducing vascular inflammatory responses under normo- and hyperglycemic conditions. The American Society for Pharmacology and Experimental Therapeutics