title: Effects of small platform catheter-based left ventricular assist device support on regional myocardial signal transduction.
abstract: OBJECTIVE
  Left ventricular (LV) assist device (LVAD) support reduces pathological loading. However, load-induced adaptive responses may be suppressed. Pathological loading dysregulates cardiac G protein-coupled receptor (GPCR) signaling. Signaling through G proteins is deleterious, whereas beta (β)-arrestin-mediated signaling is cardioprotective. We examined the effects of pathological LV loading/LV dysfunction and treatment via LVAD, on β-arrestin-mediated signaling, and genetic networks downstream of load.
  
  
  METHODS
  An ovine myocardial infarction (MI) model was used. Sheep underwent sham thoracotomy (n = 3), mid-left anterior descending coronary artery ligation to produce MI (n = 3), or MI with placement of a small-platform catheter-based LVAD (n = 3). LVAD support was continued for 2 weeks. Animals were maintained for a total of 12 weeks. Myocardial specimens were harvested and analyzed.
  
  
  RESULTS
  MI induced β-arrestin activation. Increased interactions between epidermal growth factor receptor and β-arrestins were observed. LVAD support inhibited these responses to MI (P < .05). LVAD support inhibited the activation of cardioprotective signaling effectors Akt (P < .05), and, to a lesser extent, extracellular regulated kinase 1/2 (P not significant); however, MI resulted in regional activation of load-induced GPCR signaling via G proteins, as assessed by the induction of atrial natriuretic peptide mRNA expression in the MI-adjacent zone relative to the MI-remote zone (P < .05). MI-adjacent zone atrial natriuretic peptide expression was renormalized with LVAD support.
  
  
  CONCLUSIONS
  LVAD support inhibited cardioprotective β-arrestin-mediated signaling. However, net benefits of normalization of load-induced GPCR signaling were observed in the MI-adjacent zone. These findings may have implications for the optimal extent and duration of unloading, and for the development of adjunctive medical therapies.
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md. Electronic address: Keshava.Rajagopal@uth.tmc.edu.
authors.forename: Keshava
authors.initials: K
authors.lastname: Rajagopal
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Progyaparamita
authors.initials: P
authors.lastname: Saha
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Isa
authors.initials: I
authors.lastname: Mohammed
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Pablo G
authors.initials: PG
authors.lastname: Sanchez
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Tieluo
authors.initials: T
authors.lastname: Li
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Zhongjun J
authors.initials: ZJ
authors.lastname: Wu
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine and Medical Center, Baltimore, Md.
authors.forename: Bartley P
authors.initials: BP
authors.lastname: Griffith
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006328:Cardiac Catheterization / Q000295:instrumentation*; D062906:Cardiac Catheters; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006353:Heart-Assist Devices; D008422:Materials Testing; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011474:Prosthesis Design; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020127:Recovery of Function; D012756:Sheep; D015398:Signal Transduction; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D016277:Ventricular Function, Left; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D009320:Atrial Natriuretic Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: intracellular signaling; left ventricular dysfunction; mechanical circulatory support; mechanotransduction; myocardial infarction