title: Elabela-apelin receptor signaling pathway is functional in mammalian systems.
abstract: Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.
authors: 1] Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 [2] Department of Cardiology, Nanjing Chest Hospital, Southeast University School of Medicine, Nanjing, 210029.
authors: Zhi
authors: Z
authors: Wang
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Daozhan
authors: D
authors: Yu
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892.
authors: Mengqiao
authors: M
authors: Wang
authors: Department of Internal Medicine, University of Oklahoma Health Science Center, OK 73104.
authors: Qilong
authors: Q
authors: Wang
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892.
authors: Jennifer
authors: J
authors: Kouznetsova
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Rongze
authors: R
authors: Yang
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Kun
authors: K
authors: Qian
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Wenjun
authors: W
authors: Wu
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Alan
authors: A
authors: Shuldiner
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Carole
authors: C
authors: Sztalryd
authors: Department of Internal Medicine, University of Oklahoma Health Science Center, OK 73104.
authors: Minghui
authors: M
authors: Zou
authors: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892.
authors: Wei
authors: W
authors: Zheng
authors: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Da-Wei
authors: DW
authors: Gong
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D001808:Blood Vessels / Q000502:physiology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000601133:APELA protein, human; C104575:APLNR protein, human; D000075244:Apelin Receptors; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
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