title: Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.
abstract: BACKGROUND
  MicroRNAs (miRNAs) play a key role in the development of heart failure, and recent studies have shown that the muscle-specific miR-1 is a key regulator of cardiac hypertrophy. We tested the hypothesis that chronic restoration of miR-1 gene expression in vivo will regress hypertrophy and protect against adverse cardiac remodeling induced by pressure overload.
  
  
  RESULTS
  Cardiac hypertrophy was induced by left ventricular pressure overload in male Sprague-Dawley rats subjected to ascending aortic stenosis. When the hypertrophy was established at 2 weeks after surgery, the animals were randomized to receive either an adeno-associated virus expressing miR-1 (AAV9.miR-1) or green fluorescent protein (GFP) as control (AAV9.GFP) via a single-bolus tail-vein injection. Administration of miR-1 regressed cardiac hypertrophy (left ventricular posterior wall thickness,; 2.32±0.08 versus 2.75±0.07 mm, P<0.001) and (left ventricular septum wall thickness, 2.23±0.06 versus 2.54±0.10 mm, P<0.05) and halted the disease progression compared with control-treated animals, as assessed by echocardiography (fractional shortening, 37.60±5.01% versus 70.68±2.93%, P<0.05) and hemodynamic analyses (end-systolic pressure volume relationship/effective arterial elastance, 1.87±0.46 versus 0.96±0.38, P<0.05) after 7 weeks of treatment. Additionally, miR-1 replacement therapy lead to a marked reduction of myocardial fibrosis, an improvement in calcium handling, inhibition of apoptosis, and inactivation of the mitogen-activated protein kinase signaling pathways, suggesting a favorable effect on preventing the maladaptive ventricular remodeling. We also identified and validated a novel bona fide target of miR-1, Fibullin-2 (Fbln2), a secreted protein implicated in extracellular matrix remodeling.
  
  
  CONCLUSIONS
  Taken together, our findings suggest that restoration of miR-1 gene expression is a potential novel therapeutic strategy to reverse pressure-induced cardiac hypertrophy and prevent maladaptive cardiac remodeling.
authors.affiliation: Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ioannis.karakikes@gmail.com
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Antoine H
authors.initials: AH
authors.lastname: Chaanine
authors.forename: Soojeong
authors.initials: S
authors.lastname: Kang
authors.forename: Bertrand N
authors.initials: BN
authors.lastname: Mukete
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D005355:Fibrosis; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use*; D020929:Mitogen-Activated Protein Kinase Kinases; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; C084612:fibulin 2; D020929:Mitogen-Activated Protein Kinase Kinases