title: Post-transcriptional regulation of α-1-antichymotrypsin by microRNA-137 in chronic heart failure and mechanical support.
abstract: BACKGROUND
  Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail.
  
  
  RESULTS
  Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells.
  
  
  CONCLUSIONS
  High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
authors: Department of Cardiology, University Medical Center, Utrecht, The Netherlands. s.lok@umcutrecht.nl
authors: Sjoukje I
authors: SI
authors: Lok
authors: Alain
authors: A
authors: van Mil
authors: Niels
authors: N
authors: Bovenschen
authors: Petra
authors: P
authors: van der Weide
authors: Joyce
authors: J
authors: van Kuik
authors: Dick
authors: D
authors: van Wichen
authors: Ton
authors: T
authors: Peeters
authors: Erica
authors: E
authors: Siera
authors: Bjorn
authors: B
authors: Winkens
authors: Joost P G
authors: JP
authors: Sluijter
authors: Pieter A
authors: PA
authors: Doevendans
authors: Paula A
authors: PA
authors: da Costa Martins
authors: Nicolaas
authors: N
authors: de Jonge
authors: Roel A
authors: RA
authors: de Weger
mesh_terms: D000328:Adult; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000097:blood; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D040901:Proteomics; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000235:genetics*; D014162:Transfection; D020257:Ventricular Remodeling / Q000502:physiology; D000514:alpha 1-Antichymotrypsin / Q000097:blood / Q000235:genetics*
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin; D008156:Luciferases
keywords: ACT; LVAD; heart failure; remodeling; serpina-3