Abstract
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.
Footnotes
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This study was supported by the European Union Program EWA [Grant LSHM-CT-2005-518245]; by the National Institutes of Health [Grant R01-AG027713-01]; and by Italian Ministry of University and Research, Progetti di Ricerca de Interesse Nazionale [Grant 20006065483_003].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143511.
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ABBREVIATIONS: ER, estrogen receptor; SMC, smooth muscle cell; STZ, streptozotocin; iNOS, inducible nitric-oxide synthase; E2,17β-estradiol; PPT, 4,4′,4′′-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; DPN, diarylpropionitrile; ERK, extracellular signal-regulated kinase; PD98059, 2′-amino-3′-methoxyflavone; KO, knockout; FCS, fetal calf serum; M199, medium 199; ANOVA, analysis of variance; MEK, mitogen-activated protein kinase kinase.
- Received July 14, 2008.
- Accepted October 1, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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