Browsing by Author "Albrecht, Marjorie E."

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    17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension
    (APS Journals, 2016-08-01) Lahm, Tim; Frump, Andrea L.; Albrecht, Marjorie E.; Fisher, Amanda J.; Cook, Todd G.; Jones, Thomas J.; Yakubov, Bakhtiyor; Whitson, Jordan; Fuchs, Robyn K.; Liu, Aiping; Chesler, Naomi C.; Brown, M. Beth; Medicine, School of Medicine
    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.
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    The Effect of 17beta Estradiol on Glut1 Expression In The Right Ventricle Of Rats With Severe Pulmonary Hypertension
    (Office of the Vice Chancellor for Research, 2013-04-05) Taylor, Vanessa N.; Lahm, Tim; Cucci, Anthony; Petrache, Irina; Albrecht, Marjorie E.; Brown, Mary Beth; Chingombe, Tsungai J.; Gaidoo, Richard G.
    Pulmonary 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.
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    Estrogen receptor-dependent attenuation of hypoxia-induced changes in the lung genome of pulmonary hypertension rats
    (SAGE Journals, 2017-3-27) Frump, Andrea L.; Albrecht, Marjorie E.; McClintick, Jeanette N.; Lahm, Tim; Medicine, School of Medicine
    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.