Nanoparticle-mediated delivery of irbesartan reduces myocardial ischemia/reperfusion injury in mice via pparγ -dependent mechanisms
Nanoparticle-Mediated Delivery of Irbesartan Reduces Myocardial
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 . Novel drug delivery system might overcome
insufficient therapeutic efficacy of current medicines for IR
injury . 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 - .
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
 Derek M. Yellon, Derek J. Hausenloy. Myocardial Reperfusion Injury.
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 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
 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
 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,
 Leuschner F, Dutta P, Gorbatov R, et al. Therapeutic siRNA silencing
Higashi-ku, Fukuoka, Japan (corresponding author to provide phone:
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