Abstract 15712: Nanoparticle-Mediated Targeting of Cyclosporine A to Mitochondria in Reperfused Myocardium Enhances Cardioprotection From Ischemia-Reperfusion Injury
Background: The opening of the mitochondrial permeability transition pore (mPTP) plays a critical role in myocardial ischemia-reperfusion (IR) injury. However, the cardioprotective effects of cyclosporine A (CsA), an inhibitor of mPTP, are not satisfactory when administered intravenously at the time of reperfusion in patients with acute myocardial infarction, suggesting insufficient targeting of CsA into the mitochondria in those settings. Therefore, we hypothesized that nanoparticle-mediated targeting of CsA to the mitochondria enhances the CsA-induced cardioprotection from IR injury.
Methods and Results: We prepared poly(lactic acid/glycolic acid) nanoparticle containing CsA (CsA-NP) or FITC (FITC-NP). In cultured neonatal rat cardiomyocytes, no uptake of FITC-NP was noted in normal cardiomyocytes, while mitochondrial uptake of FITC-NP was noted in fragmented mitochondria from injured cardiomyocytes by oxidative stress due to hydrogen peroxide (Fig. A). In a murine model of myocardial IR injury, intravenous administration of FITC-NP or CsA-NP at the time of reperfusion attained significantly higher FITC signals/CsA concentrations in the mitochondria of IR myocardium as compared with those in a non-ischemic myocardium (Fig. B and C). Importantly, CsA-NP treatment at the time of reperfusion reduced myocardial infarct size at 10-fold lower concentration of CsA treatment (Fig. D). The cardioprotection afforded by CsA-NP was associated with a decreased leakage of cytochrome c from the mitochondria (Fig. E), and was blunted in mice deficient in cyclophilin D (a key molecule for mPTP opening) (Fig. F).
Conclusions: Nanoparticle-mediated targeting of CsA to the mitochondria enhanced cardioprotection from IR injury through mPTP opening in a murine model. CsA-NP can be developed as a more effective inhibitor of mPTP opening and can offer organ protection from IR injury in acute myocardial infarction and other clinical settings.
- © 2013 by American Heart Association, Inc.