ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. General Cardiovascular Medicine
A novel Angiotensin(1-7) agonist, PNA5, reduces ischemic reperfusion injury and cardiac dysfunction
Christina Hoyer-Kimura
Meredith Hay
Methajit Methawasin
Robin Polt
Victoria Salcedo
Joshua P. Fricks
Arian Piepho
Marissa Lopez-Pier
Maricela Pier
Vito A. Marino
John Peter Konhilas
University of Arizona, Tucson, United States
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Abstract
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 predicted 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(100µg/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. Hearts were stained for infarct size using 2-3-4-triphenyltetrazoliumchloride, 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 parameters of strain and dyssynchrony in regional and temporal manners. 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 mid-apical regions of the heart compared to 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 regarding the protective effects of PNA5.
Summary
Keywords
Angiotensin-(1-7) [Ang-(1-7)], Fibrosis, Inflammation, ischemic reperfusion injury, PNA5, Speckle echocardiography
Received
16 December 2025
Accepted
30 January 2026
Copyright
© 2026 Hoyer-Kimura, Hay, Methawasin, Polt, Salcedo, Fricks, Piepho, Lopez-Pier, Pier, Marino and Konhilas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Christina Hoyer-Kimura; John Peter Konhilas
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