title: MicroRNA-9 is an activation-induced regulator of PDGFR-beta expression in cardiomyocytes.
abstract: The platelet derived growth factor receptor (PDGFR) is an important target for novel anti-cancer therapeutics, but agents targeting PDGFR have been associated with cardiotoxicity. Cardiomyocyte PDGFR-β signaling in pressure-overloaded hearts induces compensatory angiogenesis via a paracrine-signaling cascade. Tight regulation of receptor tyrosine kinases in response to ligand stimulation is a critical part of any such cascade. The objective of the present study was to characterize the early and late regulation of PDGFR-β following ligand stimulation and define a potential role for microRNAs (miRNAs) predicted to interact with the 3'UTR of PDGFR-β in feedback regulation. Using two in-vitro model systems (U87 glioblastoma cells and neonatal cardiomyocytes), we observed that in response to stimulation with PDGF-BB, levels of PDGFR-β declined beginning at one hour, persisting for 48 h. PDGFR-β mRNA levels declined beginning at 6h after receptor activation. Early, but not late activation-induced receptor downregulation was proteasome dependent. Levels of miRNA-9 (miR-9) were significantly increased in U87 cells and cardiomyocytes beginning 6h after addition of ligand. In response to pressure overload, miR-9 levels were significantly reduced in the hearts of cardiac-specific PDGFR-β knockout mice. Luciferase reporter assays demonstrate that miR-9 directly interacts with its predicted seed in the 3'UTR of PDGFR-β. Increasing miR-9 levels reduces levels of PDGFR-β, resulting in a reduction in the paracrine angiogenic capacity of cardiomyocytes, consistent with the established function of cardiomyocyte PDGFR-β. Importantly, increase of anti-miR-9 in cardiomyocytes attenuates ligand-induced PDGFR-β downregulation. In conclusion, we have identified miR-9 as an activation-induced regulator of PDGFR-β expression in cardiomyocytes that is part of a negative feedback loop which serves to modulate PDGFR-β expression upon ligand-stimulation through direct interaction with the 3'UTR of PDFGR-β. This article is part of a Special Issue entitled 'Possible Editorial'.
authors.affiliation: Department of Cardiology, UT M.D. Anderson Cancer Center, USA.
authors.forename: Jianhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Vishnu
authors.initials: V
authors.lastname: Chintalgattu
authors.forename: Tiffany
authors.initials: T
authors.lastname: Shih
authors.forename: Di
authors.initials: D
authors.lastname: Ai
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Aarif Y
authors.initials: AY
authors.lastname: Khakoo
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009843:Oligoribonucleotides / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D009843:Oligoribonucleotides; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta; D046988:Proteasome Endopeptidase Complex