title: Inhibition of let-7 augments the recruitment of epicardial cells and improves cardiac function after myocardial infarction.
abstract: Heart failure due to myocardial infarction is a major cause of mortality. The microRNA (miR) family let-7 is expressed during embryonic development and is up-regulated in differentiated cells. The aim of this study was to study the role of let-7 after acute myocardial infarction (AMI). We designed an antimiR to inhibit the highest expressed members of the let-7 family, let-7 a, b and c. Administration at day 0 and day 2 after AMI resulted in sustained knockdown of let-7 after 28days. Let-7 inhibition prevented deterioration of cardiac functions compared to control treatment which was especially due to improvements in the infarcted, apical cardiac segments. We observed higher contents of fibrosis in the border zone as well as increased numbers of cells positive for TCF21, which is also expressed in epicardial cells. Markers were augmented after let-7 inhibition and let-7 blocked EMT in epicardial cells in vitro. Lineage tracing in TCF21(iCre/+):R26R(tdT) mice showed abundant tomato positive cells in the infarct and border zone. In conclusion, let-7 inhibition resulted in functional benefits due to an increase in recruitment of epicardial cells and EMT.
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany; Department of Cardiology, Internal Medicine III, Johann Wolfgang Goethe-University Hospital, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Timon
authors.initials: T
authors.lastname: Seeger
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Quan-Fu
authors.initials: QF
authors.lastname: Xu
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Muhly-Reinholz
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Kremp
authors.affiliation: Department of Cardiology, Internal Medicine III, Johann Wolfgang Goethe-University Hospital, Theodor Stern Kai, 7 60590 Frankfurt, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Theodor Stern Kai, 7 60590 Frankfurt, Germany. Electronic address: dimmeler@em.uni-frankfurt.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019070:Cell Lineage; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018754:Ventricular Dysfunction / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; C112923:Tcf21 protein, mouse; C542687:mirnlet7 microRNA, mouse
keywords: Cardiac regeneration; Epicardial cells; Epithelial-to mesenchymal transition; Let-7; Myocardial infarction