Distinct roles of estrogen receptor-alpha and beta in the modulation of vascular inducible nitric-oxide synthase in diabetes.
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 ER alpha and ER beta-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 ER alpha attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17beta-estradiol to aortic tissues from ER beta- but not ER alpha-knockout mice. These findings suggest a possible role for ER alpha-selective ligands in reducing vascular inflammatory responses under normo- and hyperglycemic conditions.
Cignarella
Andrea
A
Department of Pharmacology and Anaesthesiology, University of Padova, Padova, Italy.
Bolego
Chiara
C
Pelosi
Valeria
V
Meda
Clara
C
Krust
Andrée
A
Pinna
Christian
C
Gaion
Rosa Maria
RM
Vegeto
Elisabetta
E
Maggi
Adriana
A
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D004790:Enzyme Induction; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D010636:Phenols; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D009573:Nitrites; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D052247:Nitric Oxide Synthase Type II