Affiliation:
1. Department of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka Japan
2. Department of Medicine Stanford Cardiovascular Institute and Division of Cardiovascular MedicineStanford University School of Medicine CA
3. Department of Cardiovascular Research Development, and Translational Medicine Center for Disruptive Cardiovascular Innovation Kyushu University Fukuoka Japan
Abstract
Background
The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury.
Methods and Results
We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6C
high
monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury.
Conclusions
Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
23 articles.
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