title: Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines.
abstract: BACKGROUND
  Treatment with short hairpin RNA (shRNA) interference therapy targeting phosphodiesterase 5a after myocardial infarction (MI) has been shown to mitigate post-MI heart failure. We investigated the mechanisms that underpin the beneficial effects of PDE5a inhibition through shRNA on post-MI heart failure.
  
  
  METHODS
  An adenoviral vector with an shRNA sequence inserted was adopted for the inhibition of phosphodiesterase 5a (Ad-shPDE5a) in vivo and in vitro. Myocardial infarction (MI) was induced in male C57BL/6J mice by left coronary artery ligation, and immediately after that, the Ad-shPDE5a was injected intramyocardially around the MI region and border areas.
  
  
  RESULTS
  Four weeks post-MI, the Ad-shPDE5a-treated mice showed significant mitigation of the left ventricular (LV) dilatation and dysfunction compared to control mice. Infarction size and fibrosis were also significantly reduced in Ad-shPDE5a-treated mice. Additionally, Ad-shPDE5a treatment decreased the MI-induced inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β1, which was confirmed in vitro in Ad-shPDE5a transfected myofibroblasts cultured under oxygen glucose deprivation. Finally, Ad-shPDE5a treatment was found to activate the myocardial Akt signaling pathway in both in vivo and in vitro experiments.
  
  
  CONCLUSIONS
  These findings indicate that PDE5a inhibition by Ad-shPDE5a via the Akt signal pathway could be of significant value in the design of future therapeutics for post-MI heart failure.
authors.affiliation: Department of Cardiology, the First Hospital of Qiqihaer City, Qiqihaer, China.|Department of Cardiology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.affiliation: Collaborative Innovation Center of Judicial Civilization, China, Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, the First Hospital of Qiqihaer City, Qiqihaer, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of EICU, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Lab Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio, 45267, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Paul
authors.affiliation: Department of Pathology and Lab Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio, 45267, United States of America.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D058986:Phosphodiesterase 5 Inhibitors; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse