Estrogen receptor-dependent attenuation of hypoxia-induced changes in the lung genome of pulmonary hypertension rats

17β-estradiol (E2) exerts complex and context-dependent effects in pulmonary hypertension. In hypoxia-induced pulmonary hypertension (HPH), E2 attenuates lung vascular remodeling through estrogen receptor (ER)-dependent effects; however, ER target genes in the hypoxic lung remain unknown. In order to identify the genome regulated by the E2-ER axis in the hypoxic lung, we performed a microarray analysis in lungs from HPH rats treated with E2 (75 mcg/kg/day) ± ER-antagonist ICI182,780 (3 mg/kg/day). Untreated HPH rats and normoxic rats served as controls. Using a false discovery rate of 10%, we identified a significantly differentially regulated genome in E2-treated versus untreated hypoxia rats. Genes most upregulated by E2 encoded matrix metalloproteinase 8, S100 calcium binding protein A8, and IgA Fc receptor; genes most downregulated by E2 encoded olfactory receptor 63, secreted frizzled-related protein 2, and thrombospondin 2. Several genes affected by E2 changed in the opposite direction after ICI182,780 co-treatment, indicating an ER-regulated genome in HPH lungs. The bone morphogenetic protein antagonist Grem1 (gremlin 1) was upregulated by hypoxia, but found to be among the most downregulated genes after E2 treatment. Gremlin 1 protein was reduced in E2-treated versus untreated hypoxic animals, and ER-blockade abolished the inhibitory effect of E2 on Grem1 mRNA and protein. In conclusion, E2 ER-dependently regulates several genes involved in proliferative and inflammatory processes during hypoxia. Gremlin 1 is a novel target of the E2-ER axis in HPH. Understanding the mechanisms of E2 gene regulation in HPH may allow for selectively harnessing beneficial transcriptional activities of E2 for therapeutic purposes

The Effect of 17beta Estradiol on Glut1 Expression In The Right Ventricle Of Rats With Severe Pulmonary Hypertension

poster abstractPulmonary hypertension (PH) is a devastating disease that is characterized by a rise of blood pressure in the blood vessels of the lung. This puts significant strain on the right ventricle (RV) of the heart. If untreated, PH can lead to right heart failure and death. One of the hallmarks of right heart failure in PH is the development of cytoplasmic glycolysis in the cardiac muscle cells (myocytes) of the RV. This describes a compensatory process where glucose uptake into the mitochondria is inhibited, thereby leading to its conversion to lactate in the cytoplasm. Importantly, cytoplasmic glycolysis is associated with an increase in a protein called glucose transporter 1 (Glut 1). 17beta estradiol (E2) can ameliorate experimental PH, but its effects on RV glut 1 expression are not yet known. The aim of this project is to determine the RV expression of Glut 1 in a rat model of severe PH, and to investigate whether this is decreased by E2 treatment. We assessed Glut 1 via immunofluorescence staining in cryosections of RV tissue from control rats, untreated PH rats, and E2-treated PH rats. Cell nuclei were stained with DAPI (Diamidinophenyl-indole), cell membranes were stained with WGA (wheat germ agglutinin), and Glut1 was stained with a Glut1 antibody conjugated to a red immunofluorescent dye. Nuclei are stained blue; cell membranes are stained green. Glut 1 quantification occurs via visual inspection and determination of red staining via specific software (Metamorph). We were able to successfully establish the protocol for Glut1 staining. In pilot experiments, there was little Glut1 staining present in normal RVs, but we detected up-regulation of Glut 1 in the RV of animals with PH. Whether this is affected by E2 is currently under investigation

Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice.

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p 50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation

17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg−1·day−1) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies

Trait-Based Assessments of Climate-Change Impacts on Interacting Species

Plant–animal interactions are fundamentally important in ecosystems, but have often been ignored by studies of climate-change impacts on biodiversity. Here, we present a trait-based framework for predicting the responses of interacting plants and animals to climate change. We distinguish three pathways along which climate change can impact interacting species in ecological communities: (i) spatial and temporal mismatches in the occurrence and abundance of species, (ii) the formation of novel interactions and secondary extinctions, and (iii) alterations of the dispersal ability of plants. These pathways are mediated by three kinds of functional traits: response traits, matching traits, and dispersal traits. We propose that incorporating these traits into predictive models will improve assessments of the responses of interacting species to climate change.Fil: Schleuning, Matthias. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Neuschulz, Eike Lena. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Albrecht, Jörg. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Bender, Irene Maria Antoinetta. German Centre for Integrative Biodiversity Research; Alemania. Senckenberg Biodiversity and Climate Research Centre; Alemania. Martin-Luther University. Institute of Biology, Geobotany and Botanical Garden; AlemaniaFil: Bowler, Diana E.. German Centre for Integrative Biodiversity Research; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Dehling, D. Matthias. University of Canterbury; Nueva ZelandaFil: Fritz, Susanne A.. Goethe Universitat Frankfurt; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Hof, Christian. Universitat Technical Zu Munich; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Mueller, Thomas. Goethe Universitat Frankfurt; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Nowak, Larissa. Goethe Universitat Frankfurt; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Sorensen, Marjorie C.. Goethe Universitat Frankfurt; Alemania. University of Guelph; Canadá. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Böhning Gaese, Katrin. Goethe Universitat Frankfurt; Alemania. Senckenberg Biodiversity and Climate Research Centre; AlemaniaFil: Kissling, W. Daniel. University of Amsterdam; Países Bajo

Natural effusions: Mrs J. Howorth’s English translation of Albrecht von Haller’s Die Alpen

Albrecht von Haller's Die Alpen [The Alps] was an immensely popular piece of early eighteenth-century poetry, yet it took more than half a century to be translated into English. In this article I examine Mrs J. Howorth's prose rendering of it in her translated collection The Poems of Baron Haller (1794) and analyse how the translation itself reflects late-eighteenth-century scientific, political and aesthetic concerns, notably through the influence of Linnaeus and Jean-Jacques Rousseau. Secondly, I explore how Howorth constructed a public image of herself as a female consumer and producer of botanical literature, and argue that her translation constitutes an early example of British women's increasing engagement in science through the activity of translation

História como alegoria

Neste artigo abordam-se as diferentes circunstâncias nas quais se tecem comentários sobre um evento (geralmente no passado) quando os comentadores estão, na verdade, preocupados com um outro evento (geralmente no presente). Nele, distingue-se a alegoria pragmática - que se encontra onde quer que haja restrições à liberdade de agilidade política - da alegoria mística - que pressupõe algum tipo de conexão oculta entre os dois acontecimentos. Este segundo tipo de alegoria entrou em declínio no fim do século xvii, mas poderá permanecer mais influente do que todos nós pensamos.<br>This article is concerned with the different circunstances in wich comments are made as one event (usually in the past) when the commentators are really preoccupied with another (usually in the present). It distinguishes pragmatic allegory, to be found whenever there are restrictions on freedom of political speed, from mystical allegory, which assumes some kind of occult connection between the two events. This second kind of allegory has been in decline since the end of the seventeenth century, but it may remain more influential on us all than we think