title: Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice.
abstract: The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2-positive fibroblasts, while the number of c-kit(+) cardiac stem cells and Ki-67(+) proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Tolonen
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabó
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Pirkko
authors.initials: P
authors.lastname: Viitala
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine Philadelphia, Pennsylvania.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Moilanen
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Pauli
authors.initials: P
authors.lastname: Ohukainen
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Vainio
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine Philadelphia, Pennsylvania.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland ; Medical Research Center Oulu Oulu, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland ; Division of Pharmacology and Pharmacotherapy, University of Helsinki Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu Oulu, Finland ; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu Oulu, Finland.
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
keywords: Apoptosis; Let-7c; fibroblast; heart failure; microRNA; remodeling