title: MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.
abstract: Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Sprague-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an approximately 40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1.
authors.affiliation: Department of Surgery, Vascular Medicine Institute and McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology; D018952:Antigens, CD34 / Q000032:analysis / Q000502:physiology; D015153:Blotting, Western; D016922:Cellular Senescence / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000032:analysis / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology; D010455:Peptides / Q000032:analysis / Q000502:physiology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000502:physiology; D000071161:Forkhead Box Protein O1
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D010455:Peptides; D012313:RNA; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D040301:Vascular Endothelial Growth Factor Receptor-2; C000606025:Prom1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C488368:Sirt1 protein, rat