title: Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse.
abstract: BACKGROUND
  Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI).
  
  
  METHODS
  AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement.
  
  
  RESULTS
  Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size.
  
  
  CONCLUSIONS
  Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.
authors.affiliation: School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. bvantassell@vcu.edu
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Seropian
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Lisa
authors.initials: L
authors.lastname: Smithson
authors.forename: Amit
authors.initials: A
authors.lastname: Varma
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Christopher
authors.initials: C
authors.lastname: Gelwix
authors.forename: Vinh
authors.initials: V
authors.lastname: Chau
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology / Q000627:therapeutic use; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D053583:Interleukin-1beta; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; C525002:ST2825; D013141:Spiro Compounds