Estrogen and insulin-like-growth factor 1 (IGF-1) are potent mitogenic stimuli that share important properties in the control of cellular proliferation. However, the coupling between the signaling cascades of estrogen receptors ␣ and ␤ and the IGF-1 receptor (IGF-1R) is poorly understood. Therefore, we selectively transfected estrogen receptor ␣ or ␤ in COS7 and HEK293 cells, which contain IGF-1R. In presence of estrogen receptor ␣ but not ␤, 17␤-estradiol (E2) rapidly induces phosphorylation of the IGF-1R and the extracellular signal-regulated kinases 1/2. Furthermore, upon stimulation with E2, estrogen receptor ␣ but not ␤ bound rapidly to the IGF-1R in COS7 as well as L6 cells, which express all investigated receptors endogenously. Control experiments in the IGF-1R-deficient fibroblast cell line R ؊ showed that after stimulation with E2 only estrogen receptor ␣ bound to the transfected IGF-1R. Overexpression of dominant negative mitogen-activated protein kinases kinase inhibited this effect. Finally, estrogen receptor ␣ but not ␤ is required to induce the activation of the estrogen receptor-responsive reporter ERE-LUC in IGF-1-stimulated cells. Taken together, these data demonstrate that ligand bound estrogen receptor ␣ is required for rapid activation of the IGF-1R signaling cascade.Estrogen as well as insulin-like growth factor 1 (IGF-1) 1 are potent mitogens that are involved in a large array of processes that control proliferation and differentiation in mammalian cells (1, 2). Both mitogens act through receptor-mediated signaling pathways. The cross-talk between these two signaling pathways is currently under investigation (3-6). Estrogen is a steroid hormone that binds to members of the nuclear receptor superfamily (7), whereas IGF-1 as a peptide-growth factor binds to a transmembrane tyrosine kinase receptor, which signals via a series of phosphorylation events (2).Two different estrogen receptors, ER␣ and ER␤, which are encoded by genes located on different chromosomes, have been identified so far (8,9). Sequence analysis demonstrates a high degree of homology between ER␣ and ER␤ in the DNA-binding domain and the ligand-binding domain. However, there are significant differences in regions that would be expected to influence transcriptional activity. The ability of estrogen receptors to activate target gene transcription has been attributed to two regions: the N-terminal activation function 1 (AF-1) and the ligand-dependent AF-2, which is localized in the C-terminal hormone-binding domain (10, 11). AF-1 and AF-2 can activate transcription independently and synergistically, and they act in a promoter-and cell-specific manner (12, 13). Phosphorylation of a serine residue at position 118 is required for full action of the AF-1 (14). Both AF-1 and AF-2 are required to enhance transcription of target genes through AP-1 sites (15). Interestingly, ER␣ and ER␤ act differently at AP-1 sites (16), which may be due to differences in their AF domains (17). ER␣ and ER␤ can form homo-and heterodimers (18), and thus t...

Background-The AT 1 receptor has been implicated in the pathogenesis of hypertension and atherosclerosis. Estrogen deficiency is also associated with cardiovascular diseases. Therefore, we examined the AT 1 receptor gene expression in ovariectomized rats with and without estrogen replacement therapy and the influence of estrogen on AT 1 receptor expression in cultured vascular smooth muscle cells. Methods and Results-Rat aortic tissue was examined 5 weeks after ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered during the 5-week period. Functional experiments assessed angiotensin II-induced contraction of aortic rings. AT 1 receptor mRNA levels were measured by quantitative polymerase chain reaction and Northern blotting. AT 1 receptor density was assessed by radioligand binding assays. These techniques were also applied in cultured vascular smooth muscle cells. The efficacy of angiotensin II on vasoconstriction was significantly increased in aortas from ovariectomized rats. As assessed by radioligand binding assays, AT 1 receptor density was increased to 160% without changes in receptor affinity during estrogen deficiency. AT 1 receptor mRNA levels were consistently increased to 187% in ovariectomized rats compared with sham-operated animals. Estrogen substitution therapy in ovariectomized rats reversed this AT 1 receptor overexpression. To explore the underlying mechanisms, the direct influence of estradiol on AT 1 receptor expression was investigated in VSMCs. Estradiol (1 mol/L) led to a time-dependent downregulation of AT 1 receptor mRNA, with a maximum of 33.3% at 12 hours. There was a correlative decrease in AT 1 receptor density. Conclusions-This novel observation of estrogen-induced downregulation of AT 1 receptor expression could explain the association of estrogen deficiency with hypertension and atherosclerosis, because activation of the AT 1 receptor plays a key role in the regulation of blood pressure, fluid homeostasis, and vascular cell growth. (Circulation. 1998;97:2197-2201.)Key Words: angiotensin Ⅲ hypertension Ⅲ hormones Ⅲ genes Ⅲ muscle, smooth Ⅲ atherosclerosis T he low incidence of vascular diseases in premenopausal women and the rapid increase of the risk of cardiovascular events after menopause as well as the beneficial effects of estrogen replacement therapy on cardiac and vascular morbidity have suggested a important role of estrogens in the pathogenesis of atherosclerosis. [1][2][3] In addition to its effects on classic cardiovascular risk factors, eg, in the sense of a decrease of cholesterol plasma levels, 4,5 estrogen has been recognized to directly influence vascular as well as myocardial cells. Indeed, VSMCs, myocytes, and cardiac fibroblasts have been shown to contain functional estrogen receptors. [6][7][8] Moreover, there is increasing evidence that estrogen interferes with the RAS. The production of angiotensinogen is enhanced, whereas ACE levels are decreased, by estrogens. According to a recent report, plasma renin levels are also reduced during estroge...

Gender-based differences found in cardiovascular diseases raise the possibility that estrogen may have direct effects on cardiac tissue. Therefore we investigated whether cardiac myocytes and fibroblasts express functional estrogen receptors. Immunofluorescence demonstrated estrogen receptor protein expression in both female and male rat cardiac myocytes and fibroblasts. Nuclear translocation of the estrogen receptor protein was observed after stimulation of cardiomyocytes with 17ß-estradiol (E 2 ). Cells transfected with an estrogen-responsive reporter plasmid showed that treatment with E 2 induced a significant increase in reporter activity. Furthermore, E 2 induced a significant increase in expression of the estrogen receptors a and ß, progesterone receptor and connexin 43 in cardiac myocytes. Cardiac myocytes and fibroblasts contain functional estrogen receptors and estrogen regulates expression of specific cardiac genes. These data suggest that gender-based differences in cardiac diseases may in part be due to direct effects of estrogen on the heart.

Airway hypersecretion is mediated by increased release of inflammatory mediators and can be improved by inhibition of mediator production. We have recently reported that 1.8-cineol (eucalyptol) which is known as the major monoterpene of eucalyptus oil suppressed arachidonic acid metabolism and cytokine production in human monocytes. Therefore, the aim of this study was to evaluate the anti-inflammatory efficacy of 1.8-cineol by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to receive either 200 mg 1.8-cineol t. i.d. or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of this investigation was to establish the oral glucocorticosteroid-sparing capacity of 1.8-cineol in severe asthma. Reductions in daily prednisolone dosage of 36% with active treatment (range 2.5-10 mg, mean: 3.75 mg) vs. a decrease of only 7% (2.5-5 mg, mean: 0.91 mg) in the placebo group (P = 0.006) were tolerated. Twelve of 16 cineol vs. four out of 16 placebo patients achieved a reduction of oral steroids (P = 0.012). Long-term systemic therapy with 1.8-cineol has asignificant steroid-saving effect in steroid-depending asthma. This is the first evidence suggesting an anti-inflammatory activity of the monoterpene 1.8-cineol in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases.

These data reveal a significant upregulation of AT1 receptor gene expression by LDL in vascular smooth muscle cells through mechanisms that involve posttranscriptional mRNA stabilization. Ultimately, this AT1 receptor upregulation leads to an elevated functional response of vascular smooth muscle cells on angiotensin II stimulation.

For self-measurement of blood pressure to be useful, patient reporting of test results must be reliable and accurate. Until now no study directly measured the accuracy and reliability of patients' reporting of self-measured blood pressure values. Thirty hypertensive patients (69 +/- 11 years) were instructed to measure blood pressure at home over 14 days with the highly accurate Omron IC monitor and to keep a record of all readings in a patient logbook. To assess the reliability of the records, patients were not informed about the memory capacity of the device. We compared automatically stored blood pressure readings with the respective logbook entries to analyze deletion (under-reporting), addition (over-reporting), and precision of reporting of test results. The prevalent pattern was under-reporting, averaging 36% +/- 24% (3% to 89%), which occurred significantly more than over-reporting (9% +/- 11%; 0% to 38%). The precision of reporting (identical values at corresponding times) was 76% +/- 34% (0% to 100%). This observer error did not affect group comparisons of automatically stored values and logbook entries, although the estimated limits of agreement were wide. Blood pressure control, duration of hypertension, age, or previous use of self-measurement and patterns of logbook entries were not found to be predictive of the patients' reliability. Our results demonstrate a substantial observer error in the reporting of self-measured blood pressure values. This bias may be reduced by memory-equipped blood pressure devices.

Acquired hemophilia (AH) is an extremely rare condition in which autoantibodies (inhibitors) against clotting factor VIII induce acute and life-threatening hemorrhagic diathesis because of abnormal blood clotting. The mortality rate of AH is as high as 16%, and current treatment options are associated with adverse side effects. We investigated a therapeutic approach for AH called the modified BonnMalmö Protocol (MBMP). The aims of MBMP include suppression of bleeding, permanent elimination of inhibitors, and development of immune tolerance, thereby avoiding long-term reliance on coagulation products. The protocol included immunoadsorption for inhibitor elimination, factor VIII substitution, intravenous immunoglobulin, and immunosuppression. Thirty-five high-titer patients with critical bleeding who underwent MBMP were evaluated. Bleeding was rapidly controlled during 1 or 2 apheresis sessions, and no subsequent bleeding episodes occurred. Inhibitor levels decreased to undetectable levels within a median of 3 days (95% confidence interval [95% CI], 2-4 days), factor substitution was stopped within a median of 12 days (95% CI, 11-17 days), and treatment was completed within a median of 14 days (95% CI, 12-17 days). Longterm follow-up (7 months-7 years) showed an overall response rate of 88% for complete remission (CR). When cancer patients were excluded, the CR rate was 97%. (Blood. 2005;105:2287-2293)

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