title: miR-410 and miR-495 Are Dynamically Regulated in Diverse Cardiomyopathies and Their Inhibition Attenuates Pathological Hypertrophy.
abstract: Noncoding RNAs have emerged as important modulators in cardiac development and pathological remodeling. Recently, we demonstrated that regulation of the Gtl2-Dio3 noncoding RNA locus is dependent on the MEF2 transcription factor in cardiac muscle, and that two of its encoded miRNAs, miR-410 and miR-495, induce robust cardiomyocyte proliferation. Given the possibility of manipulating the expression of these miRNAs to repair the damaged heart by stimulating cardiomyocyte proliferation, it is important to determine whether the Gtl2-Dio3 noncoding RNAs are regulated in cardiac disease and whether they function downstream of pathological cardiac stress signaling. Therefore, we examined expression of the above miRNAs processed from the Gtl2-Dio3 locus in various cardiomyopathies. These noncoding RNAs were upregulated in all cardiac disease models examined including myocardial infarction (MI) and chronic angiotensin II (Ang II) stimulation, and in the cardiomyopathies associated with muscular dystrophies. Consistent with these observations, we show that the Gtl2-Dio3 proximal promoter is activated by stress stimuli in cardiomyocytes and requires MEF2 for its induction. Furthermore, inhibiting miR-410 or miR-495 in stressed cardiomyocytes attenuated the hypertrophic response. Thus, the Gtl2-Dio3 noncoding RNA locus is a novel marker of cardiac disease and modulating the activity of its encoded miRNAs may mitigate pathological cardiac remodeling in these diseases.
authors.affiliation: Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Clark
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Soichi
authors.initials: S
authors.lastname: Sano
authors.affiliation: Health Sciences Department, College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Accorsi
authors.affiliation: Health Sciences Department, College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Mahasweta
authors.initials: M
authors.lastname: Girgenrath
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology*; D009202:Cardiomyopathies / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D006706:Homeostasis / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; C000609692:MIRN410 microRNA, mouse; C547683:MIRN495 microRNA, mouse; D035683:MicroRNAs