title: MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2.
abstract: MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression. Laminar blood flow induces atheroprotective gene expression in endothelial cells (ECs) in part by upregulating the transcription factor KLF2. Here, we identified KLF2- and flow-responsive miRs that affect gene expression in ECs. Bioinformatic assessment of mRNA expression patterns identified the miR-30-5p seed sequence to be highly enriched in mRNAs that are downregulated by KLF2. Indeed, KLF2 overexpression and shear stress stimulation in vitro and in vivo increased the expression of miR-30-5p family members. Furthermore, we identified angiopoietin 2 (Ang2) as a target of miR-30. MiR-30 overexpression reduces Ang2 levels, whereas miR-30 inhibition by LNA-antimiRs induces Ang2 expression. Consistently, miR-30 reduced basal and TNF-α-induced expression of the inflammatory cell–cell adhesion molecules E-selectin, ICAM1 and VCAM1, which was rescued by stimulation with exogenous Ang2. In summary, KLF2 and shear stress increase the expression of the miR-30-5p family which acts in an anti-inflammatory manner in ECs by impairing the expression of Ang2 and inflammatory cell–cell adhesion molecules. The upregulation of miR-30-5p family members may contribute to the atheroprotective effects of shear stress.
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Shemsi
authors.initials: S
authors.lastname: Demolli
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Doebele
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Doddaballapur
authors.affiliation: Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen GmbH, Frankfurt, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lang
authors.affiliation: Institute for Vascular Signaling, Center of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Fisslthaler
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany; Division of Internal Medicine III, Cardiology, Hospital of the Goethe University, Frankfurt, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Chavakis
authors.affiliation: ILDH, Division of Medicine, University College London (UCL), London, UK.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Sciacca
authors.affiliation: Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen GmbH, Frankfurt, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Henschler
authors.affiliation: Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Medical Faculty Mannheim (CBTM), Heidelberg University, Germany.
authors.forename: Soniya
authors.initials: S
authors.lastname: Savant
authors.affiliation: Medical Faculty Mannheim (CBTM), Heidelberg University, Germany; German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Kaluza
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.. Electronic address: boon@med.uni-frankfurt.de.
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D019295:Computational Biology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018056:Hemorheology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019040:E-Selectin; C573420:ICAM1 protein, human; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C546936:SELE protein, human; D014409:Tumor Necrosis Factor-alpha; C555023:VPS51 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D033921:Vesicular Transport Proteins; D018799:Intercellular Adhesion Molecule-1
keywords: Angiopoietin; Endothelial cell; KLF2; Laminar shear stress; MicroRNA