title: Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis.
abstract: OBJECTIVE
  Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whether inhibition of MI-induced miR-375 by LNA anti-miR-375 can improve recovery after acute MI.
  
  
  RESULTS
  Ten weeks old mice were treated with either control or LNA anti miR-375 after induction of MI by LAD ligation. The inflammatory response, cardiomyocyte apoptosis, capillary density and left ventricular (LV) functional, and structural remodelling changes were evaluated. Anti-miR-375 therapy significantly decreased inflammatory response and reduced cardiomyocyte apoptosis in the ischemic myocardium and significantly improved LV function and neovascularization and reduced infarct size. Repression of miR-375 led to the activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and increased AKT phosphorylation on Thr-308 in experimental hearts. In corroboration with our in vivo findings, our in vitro studies demonstrated that knockdown of miR-375 in macrophages modulated their phenotype, enhanced PDK-1 levels, and reduced pro-inflammatory cytokines expression following LPS challenge. Further, miR-375 levels were elevated in failing human heart tissue.
  
  
  CONCLUSIONS
  Taken together, our studies demonstrate that anti-miR-375 therapy reduced inflammatory response, decreased cardiomyocyte death, improved LV function, and enhanced angiogenesis by targeting multiple cell types mediated at least in part through PDK-1/AKT signalling mechanisms.
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Venkata N S
authors.initials: VNS
authors.lastname: Garikipati
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Department of Biomedical Engineering, University of Alabama at Birmingham, 1675 University Blvd., Volker Hall G094, Birmingham, AL 35294, USA.
authors.forename: Darukeshwara
authors.initials: D
authors.lastname: Jolardarashi
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibetti
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Cimini
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Benedict
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Nickoloff
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: May M
authors.initials: MM
authors.lastname: Truongcao
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, University of Alabama at Birmingham, 1675 University Blvd., Volker Hall G094, Birmingham, AL 35294, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.|Department of Pharmacology, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.|Department of Pharmacology, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Cardiac repair; Inflammation; MiRNA; Myocardial infarction