title: Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure.
abstract: BACKGROUND
  Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options. MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to diastolic dysfunction or other forms of heart disease is currently unknown.
  
  
  RESULTS
  Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates significant changes in circulating levels of miRNAs on antimiR-208a treatment.
  
  
  CONCLUSIONS
  These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression.
authors: miRagen Therapeutics, Inc, Boulder, CO 80301, USA.
authors: Rusty L
authors: RL
authors: Montgomery
authors: Thomas G
authors: TG
authors: Hullinger
authors: Hillary M
authors: HM
authors: Semus
authors: Brent A
authors: BA
authors: Dickinson
authors: Anita G
authors: AG
authors: Seto
authors: Joshua M
authors: JM
authors: Lynch
authors: Christianna
authors: C
authors: Stack
authors: Paul A
authors: PA
authors: Latimer
authors: Eric N
authors: EN
authors: Olson
authors: Eva
authors: E
authors: van Rooij
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D006321:Heart / Q000503:physiopathology*; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D006973:Hypertension / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000097:blood; D058990:Molecular Targeted Therapy; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D051381:Rats; D020303:Rats, Inbred Dahl; D014158:Transcription, Genetic / Q000187:drug effects; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C558425:MIRN499 microRNA, rat; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; C551613:Myh7 protein, mouse; D016376:Oligonucleotides, Antisense; D018995:Myosin Heavy Chains