title: Hydrogen Peroxide-Responsive Nanoparticle Reduces Myocardial Ischemia/Reperfusion Injury.
abstract: During myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species (ROS) is produced. In particular, overproduction of hydrogen peroxide (H2O2) is considered to be a main cause of I/R-mediated tissue damage. We generated novel H2O2-responsive antioxidant polymer nanoparticles (PVAX and HPOX) that are able to target the site of ROS overproduction and attenuate the oxidative stress-associated diseases. In this study, nanoparticles were examined for their therapeutic effect on myocardial I/R injury.
  
  
  
  The therapeutic effect of nanoparticles during cardiac I/R was evaluated in mice. A single dose of PVAX (3 mg/kg) showed a significant improvement in both cardiac output and fraction shortening compared with poly(lactic-coglycolic acid) (PLGA) particle, a non-H2O2-activatable nanoparticle. PVAX also significantly reduced the myocardial infarction/area compared with PLGA (48.7±4.2 vs 14.5±2.1). In addition, PVAX effectively reduced caspase-3 activation and TUNEL-positive cells compared with PLGA. Furthermore, PVAX significantly decreased TNF-α and MCP-1 mRNA levels. To explore the antioxidant effect of PVAX by scavenging ROS, dihydroethidium staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R, whereas a number of dihydroethidium-positive cells were observed in a group with PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase (NOX) 2 and 4 expression, which favors the reduction in ROS generation after I/R.
  
  
  
  Taken together, these results suggest that H2O2-responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.|Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Park
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.|Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Changsun
authors.initials: C
authors.lastname: Kang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Dilmen
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Tae Hi
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.|Department of Cardiology, Gwangju Christian Hospital, Gwangju, South Korea.
authors.forename: Dong Goo
authors.initials: DG
authors.lastname: Kang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of Cardiology, Gwangju Christian Hospital, Gwangju, South Korea.
authors.forename: Seung Uk
authors.initials: SU
authors.lastname: Lee
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea pkang@bidmc.harvard.edu dlee@jbnu.ac.kr.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA pkang@bidmc.harvard.edu dlee@jbnu.ac.kr.|Harvard Medical School, Boston, MA.|Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D000074662:NADPH Oxidase 2 / Q000187:drug effects / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles; D018384:Oxidative Stress / Q000187:drug effects*; D011108:Polymers; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics
chemical_list: D000975:Antioxidants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011108:Polymers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: antioxidant; inflammation; ischemia reperfusion injury; nanotechnology