Nanoparticle-mediated delivery of irbesartan reduces myocardial ischemia/reperfusion injury in mice via pparγ -dependent mechanisms

Nanoparticle-Mediated Delivery of Irbesartan Reduces Myocardial ,VFKHPLD5HSHUIXVLRQ,QMXU\LQ0LFHYLD33$5-Dependent Yasuhiro Nakano, Tetsuya Matoba, Gentaro Ikeda, Kaku Nakano, Kensuke Egashira Irbesartan-NP reduced infarct size via PPAR pathway. Therapeutic effect of early myocardial reperfusion in acute myocardial infarction is limited by ischemia-reperfusion (IR) injury [1]. Novel drug delivery system might overcome insufficient therapeutic efficacy of current medicines for IR injury [2]. Here we hypothesized that nanoparticle-mediated delivery of irbesartan, an angiotensin receptor blocker that possesses a partial agonistic effect on peroxisome reperfusion ameliorates IR injury [3]- [5]. In a murine model of a 30-min myocardial IR injury, we examined cellular distribution of poly-lactic-co-glycolic acid (PLGA) nanoparticle containing fluorescein isothiocyanate (FITC-NP) or FITC solution intravenously administered 5 Figure 2. The role of AT1 receptor in infarct size after I/R. mins before reperfusion. Significant FITC fluorescence was detected in IR myocardium after the treatment with FITC-NP but not FITC solution. Flow cytometry (FCM) revealed FITC-NP uptake by monocytes and neutrophils that were recruited into the IR heart. Intravenous treatment with irbesartan-containing nanoparticle (Irb-NP, 3.0 mg/kg irbesartan) reduced infarct size 24 hours after reperfusion, which was caQFHOHG E\ WKH SUHWUHDWPHQW ZLWK 33$5 antagonist GW9662 (Fig 1). Importantly, Irb-NP was effective to reduce IR injury even in AT1-deficient mice. In losartan-containing nanoparticle (10 mg/kg losartan), or irbesartan solution (3.0 mg/kg) was ineffective (Fig 2). Irb-13 VLJQLILFDQWO\ LQFUHDVHG 33$5 DFWLYLW\ DQG decreased NF-%DFWLYLW\LQWKHQXFOHDUH[WUDFWIURP WKH ,5 myocardial tissue, which were canceled by the pretreatment with GW9662. FCM 12 hours after reperfusion revealed that Irb-NP reduced neutrophils and Ly6Chigh inflammatory [1] Derek M. Yellon, Derek J. Hausenloy. Myocardial Reperfusion Injury. N Engl J Med. 2007;357:1121-1136. [2] Abhiram Prasad, Gregg W. Stone, David R. Holmes, Bernard Gersh. NP-mediated delivery of irbesartan into leukocytes and IR Reperfusion Injury, Microvascular Dysfunction, and Cardioprotection. myocardium reduced myocardial IR injury via [3] Florian Leuschner, Filip K. Swirski, Ralph Weissleder, Matthias Nahrendorf. Angiotensin-Converting Enzyme Inhibition Prevents the Release of Monocytes From Their Splenic Reservoir in Mice With Myocardial Infarction. Circulation Research. 2010;107:1364-1373 [4] Tian-li Yue, Robin E. Buckingham and Eliot H. Ohlstein. In Vivo Myocardial Protection From Ischemia/Repefsuion Injury by the Peroxisome Proliferator-Activated Receptor- Agonist Rosiglitazone. All authors are with the Department of Cardiovascular medicine Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, [5] Leuschner F, Dutta P, Gorbatov R, et al. Therapeutic siRNA silencing Higashi-ku, Fukuoka, Japan (corresponding author to provide phone: (+81)92-642-5359; fax: (+81)92-642-5374; e-mail:

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