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Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse.

AbstractBACKGROUND:
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.
AuthorsBenjamin W Van Tassell, Ignacio M Seropian, Stefano Toldo, Fadi N Salloum, Lisa Smithson, Amit Varma, Nicholas N Hoke, Christopher Gelwix, Vinh Chau, Antonio Abbate
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 55 Issue 4 Pg. 385-90 (Apr 2010) ISSN: 1533-4023 [Electronic] United States
PMID20125030 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Heterocyclic Compounds, 2-Ring
  • Interleukin-1beta
  • Interleukin-6
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Small Interfering
  • ST2825
  • Spiro Compounds
Topics
  • Animals
  • Heart (drug effects)
  • Heart Ventricles (drug effects, pathology)
  • Heterocyclic Compounds, 2-Ring (pharmacology, therapeutic use)
  • Hypertrophy, Left Ventricular (pathology, prevention & control)
  • Interleukin-1beta (pharmacology)
  • Interleukin-6 (blood)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Myeloid Differentiation Factor 88 (antagonists & inhibitors, genetics, metabolism)
  • Myocardial Infarction (drug therapy, pathology, therapy)
  • Myocardium (metabolism, pathology)
  • NF-kappa B (metabolism)
  • RNA, Small Interfering (administration & dosage, genetics, therapeutic use)
  • Spiro Compounds (pharmacology, therapeutic use)
  • Ventricular Remodeling (drug effects)

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