PNA5 treatment improved ejection fraction to approximately 46.6% at 5 weeks post-ischemic reperfusion injury compared to 38.5% with saline (p=0.026) in male mice.
Does PNA5 improve cardiac function and reduce infarct size in a mouse model of ischemic reperfusion injury?
In a mouse model of ischemic reperfusion injury, the novel Ang-(1-7) agonist PNA5 preserved systolic function, accelerated functional recovery, and improved global longitudinal strain.
Effect estimate: p=0.026 at 5 weeks post-IR
Absolute Event Rate: 46.6% vs 38.5%
p-value: p=0.026
Introduction Ischemic heart disease, typically caused by myocardial infarction (MI), is the leading cause of death. Ischemic reperfusion (IR) injury following MI is multifaceted, driven by reactive oxidative species (ROS), calcium overload, and inflammatory responses. Because our novel glycopeptide derivative of Angiotensin-(1-7), PNA5, has an improved half-life, decreases circulating inflammatory cytokines, and inhibits endothelial ROS production, we predict that PNA5 will attenuate IR sequelae post-IR. Methods Three-month-old C57Bl/6J male mice were subjected to IR and treated subcutaneously, with PNA5 (100 µg/kg/day, n = 14) or saline ( n = 12) starting immediately after reperfusion and continued daily for 8 weeks. Echocardiograms were taken 2, 5, and 8 weeks post-IR in B-mode using the Vevo 2100 High-Resolution Imaging System (Visual Sonics, Canada). Data were analyzed using Vevo 2100® analytic software. The hearts of the mice were stained for infarct size using 2-3-4-triphenyltetrazolium chloride, fibrosis using Picrosirius Red, and inflammation via immunofluorescence for TNFα. Results Conventional transthoracic echocardiography showed early improvement in ejection fraction by 5 weeks post-IR. Using speckle echocardiography, we demonstrated that PNA5 treatment improved the parameters of strain and dyssynchrony in regional and temporal domains. Global longitudinal strain (GLS) and left ventricular dyssynchrony showed continued dysfunction in untreated animals post-IR, whereas measures of ejection fraction did not. Along with reduced infarct size, PNA5 treatment improved cardiac remodeling, evidenced by reduced scarring within the midapical regions of the heart compared with untreated animals. Conclusion These data suggest that PNA5 treatments improve heart outcomes post-IR and could potentially be a therapeutic for IR injury; measures of GLS and dyssynchrony may provide more relevant insight into the protective effects of PNA5.
Hoyer-Kimura et al. (Fri,) conducted a other in Three-month-old male C57Bl/6J mice subjected to ischemic reperfusion injury as model of myocardial infarction (n=26). PNA5, a novel synthetic glycopeptide derivative of angiotensin-(1-7) vs. Saline injections was evaluated on Cardiac function assessed by conventional transthoracic echocardiography ejection fraction (EF%) at 2, 5, and 8 weeks post-IR (p=0.026 at 5 weeks post-IR, p=0.026). PNA5 treatment improved ejection fraction to approximately 46.6% at 5 weeks post-ischemic reperfusion injury compared to 38.5% with saline (p=0.026) in male mice.
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