Anti‐thrombotic and Anti‐inflammatory Nanoparticle Limits Early Remodeling in Acute Myocardial Infarction

Abstract

Acute myocardial infarction (AMI) is a life‐threatening medical condition. Based on the statistics updated in 2017, there is a person experiencing myocardial infarction every 40 seconds. For AMI patients, majority of them miss the treatment window for rescuing significant amounts of viable myocardium. However, infarction size can expand for weeks after the initial AMI, which provides an opportunity to prevent ventricular remodeling (progressive chamber enlargement) as well as improve healing process. AMI associated secondary ischemia further induces endothelial damage, elevated propagulation status, inflammation, and extracellular collagen degradation. Accordingly, the objective of this study is to reduce early ventricular remodeling by preventing microvascular thrombosis and reducing inflammation simultaneously with PPACK (phenylalanine‐proline‐arginine chloromethylketone) perfluorocarbon (PFC) nanoparticles (NP). Benefits of delivery PPACK by PFC NP are 1) enabling formation of anticoagulation surface specifically in the damaged vessels where thrombin is activated in order to preserve vascular integrity and limit inflammation induced by thrombin signaling and 2) minimum systemic exposure to avoid the risk of bleeding. Fluorescence microscopic images demonstrated the delivery of PFC NPs to the area at risk and remain there 24 hours after the i.v. injection (n=10) (Fig. A). For all 32 mice underwent closed‐chest ischemia (LAD occlusion) for 90 min followed by 24 hrs reperfusion. Before and 24 hrs after ischemic reperfusion injury, echocardiography was performed (VEVO 2200). The results (Fig. B) demonstrated that PPACK NP treated mice exhibited marked preservation of cardiac functional parameters as early as 24 hours after ischemia as compared to control mice according to changes in contractile metrics: 1) ΔEDV%: 40%±21% vs 77%±38% for treated vs control (p=0.02) and 2) ΔESV%: 118%±43% vs 216%±108%, for treated vs control (p=0.02) (n=16/group). To better understand the therapeutic mechanism, transcriptome profile has been evaluated by using RNASeq on normal zones and border zones of AMI mice with (n=5) or without (n=4) PPACK PFC NP treatment. The results demonstrated that in the border zone after 24 hours reperfusion, PPACK PFC NP treatment attenuated inflammatory NF‐kB signaling, and reduced NF‐kB dependent proteases (MMP 8, 9, 25), which were ~2 times higher in control group (Fig C). Moreover, numerous collagen transcripts, including Col1, 5, 6, 11, 16, and 24, were significantly elevated in the treatment group (Fig D), offering protective effects in AMI. These results demonstrate that PPACK PFC nanoparticle treatment may enhance healing in AMI and preserve cardiac microarchitecture.Support or Funding InformationR01 DK102691R01 AR067491R01 HL073646‐08This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.