Abstract 16268: A Novel Multi-Targeting Approach for Myocardial Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Irbesartan Reduces Ischemia/Reperfusion Injury in Mice
Background: Therapeutic effect of early myocardial reperfusion in acute myocardial infarction is limited by ischemia-reperfusion (IR) injury. Although various pharmacological agents including angiotensin II type 1 receptor blockers (ARBs) have been tested to reduce IR injury in animals, none of them had translated into clinical practice possibly because they target one of multiple mechanisms of IR injury. Here we demonstrate a novel multi-targeting approach for IR injury by the use of nanoparticle (NP)-mediated selective delivery of irbesartan (Irb), an ARB that possesses a partial agonistic effect for peroxisome proliferator-activated receptor (PPAR)γ, into myocardial IR lesions.
Methods and Results: We examined cellular distribution of bioabsorbable polylactide/glycolide co-polymeric NP containing FITC (FITC-NP) or FITC solution in a murine model of a 30-min myocardial IR injury (Fig A). Significant FITC fluorescence was detected in IR myocardium after intravenous injection of FITC-NP 5 mins before reperfusion. No significant FITC signals were noted after injection of FITC solution. Flow cytometry (FCM) in the blood, spleen or heart revealed FITC-NP uptake by leukocytes in the IR heart (Fig B). Intravenous treatment with Irb-NP containing 3.0 mg/kg Irb reduced infarct size 24 hours after reperfusion, which was canceled by the pretreatment with PPARγ antagonist GW9662, whereas Irb solution (3.0 mg/kg) or losartan-NP (10 mg/kg) was ineffective (Fig C). Irb-NP increased PPARγ DNA binding activity in the IR heart, which was canceled by pretreatment with GW9662. Moreover, FCM 12 hours after reperfusion revealed that Irb-NP reduced Ly6Chigh inflammatory monocytes in the heart (Fig D).
Conclusions: NP-mediated delivery of Irb into IR myocardium is a novel multi-targeting therapeutic approach for myocardial IR injury by protecting cardiomyocytes and reducing monocytes infiltration/activation via PPARγ-dependent mechanisms.
- © 2012 by American Heart Association, Inc.