title: MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart.
abstract: MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA-mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. Rescue experiments revealed that the effects of miR-22 on cardiac fibroblasts were only partially mediated by mimecan. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. Our results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jazbutyte
authors.forename: Jan
authors.initials: J
authors.lastname: Fiedler
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: Paolo
authors.initials: P
authors.lastname: Galuppo
authors.forename: Annette
authors.initials: A
authors.lastname: Just
authors.forename: Angelika
authors.initials: A
authors.lastname: Holzmann
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D012313:RNA