title: Viral Vector-Based Targeting of miR-21 in Cardiac Nonmyocyte Cells Reduces Pathologic Remodeling of the Heart.
abstract: Systemic inhibition of miR-21 has proven effective against myocardial fibrosis and dysfunction, while studies in cardiac myocytes suggested a protective role in this cell type. Considering potential implications for therapy, we aimed to determine the cell fraction where miR-21 exerts its pathological activity. We developed a viral vector-based strategy for gene targeting of nonmyocyte cardiac cells in vivo and compared global to cardiac myocyte-specific and nonmyocyte-specific deletion of miR-21 in chronic left ventricular pressure overload. Murine moloney virus and serotype 9 of adeno-associated virus were engineered to encode improved Cre recombinase for genetic deletion in miR-21fl/flmice. Pericardial injection of murine moloney virus-improved Cre recombinase to neonates achieved highly selective genetic ablation of miR-21 in nonmyocyte cardiac cells, identified as cardiac fibroblasts and endothelial cells. Upon left ventricular pressure overload, cardiac function was only preserved in mice with miR-21 deficiency in nonmyocyte cardiac cells, but not in mice with global or cardiac myocyte-specific ablation. Our data demonstrate that miR-21 exerts its pathologic activity directly in cardiac nonmyocytes and encourage further development of antimiR-21 therapy toward cellular tropism.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Technische Universität München (TUM), Munich, Germany.
authors.forename: Deepak
authors.initials: D
authors.lastname: Ramanujam
authors.affiliation: Institut für Pharmakologie und Toxikologie, Technische Universität München (TUM), Munich, Germany.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.affiliation: Institut für Pharmakologie und Toxikologie, Technische Universität München (TUM), Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Laggerbauer
authors.affiliation: Institut für Pharmakologie und Toxikologie, Technische Universität München (TUM), Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Electronic address: stefan.engelhardt@tum.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D057809:HEK293 Cells; D006331:Heart Diseases / Q000235:genetics / Q000628:therapy*; D006333:Heart Failure; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008979:Moloney murine leukemia virus / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs