title: Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart.
abstract: Aim:Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results:Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-β receptor-1 (TGFβR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFβR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts.Conclusion:Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.
authors.affiliation: Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
authors.forename: Shruti
authors.initials: S
authors.lastname: Rawal
authors.affiliation: Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
authors.forename: Pujika Emani
authors.initials: PE
authors.lastname: Munasinghe
authors.affiliation: Department of Microbiology and Immunology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Prashanth Thevkar
authors.initials: PT
authors.lastname: Nagesh
authors.affiliation: Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
authors.forename: Jason Kar Sheng
authors.initials: JKS
authors.lastname: Lew
authors.affiliation: Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Jones
authors.affiliation: Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Michael J A
authors.initials: MJA
authors.lastname: Williams
authors.affiliation: Department of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Philip
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Dick
authors.initials: D
authors.lastname: Bunton
authors.affiliation: Department of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Ivor F
authors.initials: IF
authors.lastname: Galvin
authors.affiliation: Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Patrick
authors.initials: P
authors.lastname: Manning
authors.affiliation: Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
authors.forename: Regis R
authors.initials: RR
authors.lastname: Lamberts
authors.affiliation: Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand rajesh.katare@otago.ac.nz.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C505361:MIRN15 microRNA, human; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; D018125:Receptors, Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D005947:Glucose