Abstract 12674: Nanoparticles-Mediated Delivery of Irbesartan Reduces Myocardial Ischemia/Reperfusion Injury via PPAR?-Dependent Anti-Inflammatory Mechanisms in Mice
Background: Therapeutic effect of early reperfusion in acute myocardial infarction is limited by ischemia-reperfusion (IR) injury. Novel drug delivery system (DDS) might overcome insufficient therapeutic efficacy of current medicines for IR injury. Here we tested our hypothesis that nanoparticles-mediated delivery of irbesartan (Irb-NPs), an angiotensin receptor blocker that possesses a partial agonistic effect on peroxisome proliferator-activated receptor (PPAR)γ, ameliorates IR injury.
Methods and Results: In a mouse model of myocardial IR injury, flow cytometry (FCM) revealed that neutrophils and Ly6Chigh inflammatory monocytes/macrophages are predominantly recruited from 3 to 24 hrs after IR, whereas Ly6Clow monocytes/macrophages prevailed after 48 hrs (Fig A). We next examined the role of neutrophils by use of anti-Ly6G antibody and Ly6Chigh monocytes by use of CCR2 KO mice in IR injury and found that Ly6Chigh monocytes/macrophages, but not neutrophils, plays a key role in IR injury in this model (Fig B). Therefore, we utilized NPs as a DDS in this study. FCM revealed that monocytes/macrophages in the blood and heart incorporated intravenously injected FITC-NPs, but not FITC solution after IR (Fig C). Treatment with Irb-NPs (3.0 mg/kg irbesartan) reduced infarct size 24 hrs after reperfusion, which was canceled by the pretreatment with PPARγ antagonist GW9662. In contrast, Losartan-NPs (10 mg/kg losartan), or irbesartan solution (3.0 mg/kg) was ineffective. Importantly, Irb-NPs was effective to reduce IR injury in AT1R KO mice (Fig D). Irb-NPs significantly increased PPARγ activity and decreased NF-κB activity in the IR heart (Fig E). FCM revealed that Irb-NPs reduced Ly6Chigh monocytes/macrophages in the IR heart (Fig F).
Conclusions: NPs-mediated delivery of irbesartan into monocytes/macrophages and IR myocardium effectively reduced myocardial IR injury via PPARγ-dependent anti-inflammatory mechanisms.
- © 2013 by American Heart Association, Inc.