title: Vascular importance of the miR-212/132 cluster.
abstract: BACKGROUND
  Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions.
  
  
  OBJECTIVE
  The objective of this study is to identify endothelial functions of the pro-hypertrophic miR-212/132 cluster and its cross-talk with other microRNAs during development and disease.
  
  
  RESULTS
  We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo, deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice.
  
  
  CONCLUSIONS
  Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany thum.thomas@mh-hannover.de regalla.kumarswamy@mh-hannover.de.
authors.forename: Regalla
authors.initials: R
authors.lastname: Kumarswamy
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Volkmann
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Beermann
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Napp
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Jabs
authors.affiliation: Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
authors.forename: Raj
authors.initials: R
authors.lastname: Bhayadia
authors.affiliation: Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.affiliation: Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany Division of Developmental Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ucar
authors.affiliation: Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany.
authors.forename: Kamal
authors.initials: K
authors.lastname: Chowdhury
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Lorenzen
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
authors.forename: Shashi Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Sandor
authors.initials: S
authors.lastname: Batkai
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany National Heart and Lung Institute, Imperial College London, London, UK REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany thum.thomas@mh-hannover.de regalla.kumarswamy@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors; D002196:Capillaries / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; C490897:Gab1 protein, mouse; C546976:MIRN132 microRNA, mouse; C554518:MIRN212 microRNA, mouse; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Angiogenesis; Endothelial cells; MicroRNAs; Sirtuins; Vascular function