A novel angiotensin(1-7) agonist, PNA5, reduces ischemic reperfusion injury and cardiac dysfunction

TL;DR

A new drug called PNA5 improves heart function and reduces damage after heart attacks in mice.

Contribution

PNA5, a novel Angiotensin(1-7) agonist, shows therapeutic potential for ischemic reperfusion injury.

Findings

PNA5 improved ejection fraction and reduced infarct size in mice after ischemic reperfusion.

PNA5 treatment reduced cardiac scarring and improved strain and dyssynchrony measures.

PNA5 decreased inflammation and oxidative stress in post-ischemic hearts.

Abstract

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.

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.

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.

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.

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