Abnormal uterine bleeding is the major reason for discontinuing long-term progesterone-only contraceptives (LTPOCs). Prior studies demonstrated that endometria exposed to the LTPOC, Norplant, display aberrant angiogenesis, leukocyte infiltration, and hypoxia-associated impaired blood flow. Paradoxically, human endometrial stromal cells (HESCs) of these specimens exhibit elevated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation. The current study demonstrates that TF levels are also elevated in HESCs that are decidualized after insertion of Mirena, an intrauterine system that releases levonorgestrel directly into the endometrial canal and produces elevated perivascular levels of the proinflammatory and angiognenic cytokine IL-8. Because bleeding, inflammation, and ischemia-associated increased vascular permeability enhance access of plasma factor VII to HESC-expressed TF to generate thrombin, we evaluated the effects of steroids, thrombin, and hypoxia on HESC expression of IL-8. Confluent HESCs were incubated in a serum-containing medium for 7 d with vehicle control or estradiol (E(2)) plus medroxyprogesterone acetate (MPA). The medium was then exchanged for corresponding defined medium with and without thrombin, and the cultures were incubated in parallel for up to 48 h in a standard incubator (normoxia) or a sealed chamber at 0-1% O(2) (hypoxia). Under normoxia, immunoreactive IL-8 levels in the conditioned medium were reduced to one-third of control levels during decidualization with E(2)+MPA (P < 0.05; n = 5). In E(2)+MPA-treated cultures, thrombin (0.1 U/ml to 2.5 U/m) elicited a dose-dependent reversal of this inhibition, elevating IL-8 up to 60-fold (P < 0.05; n = 5) for more than 24 h and steady-state IL-8 mRNA levels by 3-fold for 3 h. The specific inactivator, hirudin, blocked most of the effects of thrombin, whereas TRAP-14, an agonist of the protease-activated receptor for thrombin, enhanced IL-8 output. In the absence of thrombin, hypoxia elevated IL-8 output 5-fold in E(2)+MPA-treated HESCs (P < 0.02, n = 4), with thrombin exerting additive effects. In contrast to its effects in progestin-treated HESCs, hypoxia did not elevate IL-8 output in control cultures. This study suggests that inhibition of IL-8 expression in decidualized HESCs contributes to the antiinflammatory milieu of the luteal phase. However, LTPOC-induced hypoxia and excess thrombin generation enhance IL-8 expression in decidualized HESCs, thereby eliciting aberrant angiogenesis and inflammation that promote the onset of abnormal uterine bleeding.
Danzi, Sara, Peter Dubon, and Irwin Klein. Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation. Am J Physiol Heart Circ Physiol 289: H1506 -H1511, 2005. First published May 13, 2005; doi:10.1152/ajpheart.00182.2005.-Thyroid hormone regulates the transcription of several important cardiac genes. Although the thyroid gland produces predominantly thyroxine (T4), it is triiodothyronine (T3) that is transported across the sarcolemma and binds to nuclear thyroid hormone receptor proteins; yet various studies suggest that serum T 3 levels do not accurately reflect cellular T 3 action. To address this question, we studied the dose-response relationship of T 3 administered by constant infusion in hypothyroid animals with the simultaneous in vivo transcription rate of the cardiac-specific ␣-myosin heavy chain (MHC) gene, measured by quantitating ␣-MHC heteronuclear (hn)RNA content. Constant infusion of 4 g T 3 ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 for 3 days normalized serum T 3 and restored transcription to euthyroid levels; in contrast, daily injections of the same dose increased ␣-MHC transcription by only 55% of that obtained by infusion. Although infusion of T 3 at 1.25 g T 3 ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 was not sufficient to restore serum T3 to normal, it was capable of restoring transcription to normal at 3 days, but when administered for 12 days, transcription of ␣-MHC was found to be 50% of euthyroid levels, demonstrating a decreased sensitivity to T 3 over time. Treatment with trichostatin A (TSA) to inhibit histone deacetylation increased levels of total nuclear acetylated histone H4 by almost 50% but was without effect on the real-time PCR measures of ␣-MHC hnRNA. TSA administered together with T 3 (10 g T3/kg body wt) significantly increased transcription of ␣-MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T 3 regulation of cardiac ␣-MHC transcription. heteronuclear RNA; thyroid hormone; transcription; trichostatin A THYROID HORMONE EXERTS well-defined effects on the heart and the cardiovascular system (16). Triiodothyronine (T 3 ) has been shown to act on the cardiac myocyte via genomic (nuclear) and nongenomic pathways (11,16). The cellular genomic mechanisms of T 3 action on positively regulated myocyte genes [␣-myosin heavy chain (MHC) and sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2] have been well described (11,20). T 3 binds to nuclear thyroid hormone receptors (TRs), which in turn bind to thyroid hormone response elements in the promoter region of thyroid hormone-responsive genes. In the presence of T 3 , TRs activate transcription by recruiting coactivator complexes, and in the absence of T 3 , TRs repress transcription by recruiting corepressor complexes (29). Despite the fact that T 3 is the biologically active form of thyroid hormone, studies have shown that normalizing serum T 3 in hypothyroid animals by administration of thyroxine (T 4 ), T 3 , or a combination of T 4 and T 3 does not necessarily normalize T 3 content...
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