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.
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: Eleonora Mezzaroma; Stefano Toldo; Daniela Farkas; Ignacio M Seropian; Benjamin W Van Tassell; Fadi N Salloum; Harsha R Kannan; Angela C Menna; Norbert F Voelkel; Antonio Abbate Journal: Proc Natl Acad Sci U S A Date: 2011-11-21 Impact factor: 11.205
Authors: Ignacio M Seropian; Juan P Cerliani; Stefano Toldo; Benjamín W Van Tassell; Juan M Ilarregui; Germán E González; Mirian Matoso; Fadi N Salloum; Ryan Melchior; Ricardo J Gelpi; Juan C Stupirski; Alejandro Benatar; Karina A Gómez; Celina Morales; Antonio Abbate; Gabriel A Rabinovich Journal: Am J Pathol Date: 2012-11-09 Impact factor: 4.307
Authors: Stefano Toldo; Eleonora Mezzaroma; Matthew D McGeough; Carla A Peña; Carlo Marchetti; Chiara Sonnino; Benjamin W Van Tassell; Fadi N Salloum; Norbert F Voelkel; Hal M Hoffman; Antonio Abbate Journal: Cardiovasc Res Date: 2014-12-18 Impact factor: 10.787
Authors: Stefano Toldo; Eleonora Mezzaroma; Benjamin W Van Tassell; Daniela Farkas; Carlo Marchetti; Norbert F Voelkel; Antonio Abbate Journal: Exp Physiol Date: 2012-11-23 Impact factor: 2.969