ABSTRACT
It has been reported that various endocrine hormones exert prominent effects on erythropoiesis. We conducted experiments to identify the mechanisms involved in the regulatory functions of adrenergic signaling on erythroid differentiation and the expression of hemoglobin genes. The reactivation of fetal hemoglobin (HbF) expression is also an important therapeutic option in patients with hemoglobin disorders. We determined that the adrenergic agonists phenylephrine (PE) and isoproterenol (ISO) can induce the production of ß-hemoglobin embryonic 1 (hbbe1) mRNA and protein in adult zebrafish erythrocytes. Elevated levels of HbF mRNA and protein were also observed in human K562 cells after the adrenergic agonist treatments. In addition, elevated levels of histone acetylation were observed in both the PE- and the ISO-treated K562 cells. Additionally, our data further indicate that the induction effects of the adrenergic agonists on HbF synthesis and erythroid differentiation in K562 cells are mainly mediated by the p38 MAPK/cAMP response element binding pathway. In summary, the present study identifies the role of the adrenergic agonists PE and ISO on p38 MAPK and ERK signaling for the stimulation of HbF production and erythroid differentiation.
Subject(s)
Cell Differentiation , Erythroid Cells/cytology , Fetal Hemoglobin/metabolism , Isoproterenol/pharmacology , Phenylephrine/pharmacology , Animals , Cell Line , Fetal Hemoglobin/genetics , Gene Expression Regulation , Histones/genetics , Histones/metabolism , Humans , Leukemia, Erythroblastic, Acute/metabolism , MAP Kinase Signaling System , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Zebrafish , beta-Globins/genetics , beta-Globins/metabolism , gamma-Globins/genetics , gamma-Globins/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for "reverse triglyceride transportation" similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both alpha-adrenergic agonist, phenylephrine (PE) and beta-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the beta-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well.
