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A novel angiotensin(1-7) agonist, PNA5, reduces ischemic reperfusion injury and cardiac dysfunction
Christina Hoyer-Kimura1, Meredith Hay1,2,3, Methawasin Methajit4
1Department of Physiology, The University of Arizona, Tucson, AZ, United States.
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.
Insights
PNA5, a novel Angiotensin-(1-7) derivative, significantly improved heart function and reduced cardiac damage following ischemic reperfusion injury in mice. This therapeutic shows promise for treating heart conditions caused by myocardial infarction.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Regenerative Medicine
Background:
- Ischemic heart disease, primarily myocardial infarction (MI), is a leading global cause of mortality.
- Ischemic reperfusion (IR) injury exacerbates MI damage through oxidative stress, calcium overload, and inflammation.
- Existing treatments for IR injury have limitations in fully restoring cardiac function.
Purpose of the Study:
- To evaluate the therapeutic potential of PNA5, a novel glycopeptide derivative of Angiotensin-(1-7), in attenuating IR injury.
- To assess PNA5's effects on cardiac function, infarct size, fibrosis, and inflammation post-IR.
- To investigate PNA5's impact on key echocardiographic parameters, including global longitudinal strain (GLS) and dyssynchrony.
Main Methods:
- Male C57Bl/6J mice underwent IR injury and were treated with PNA5 (100 µg/kg/day) or saline for 8 weeks.
- Cardiac function was assessed using serial echocardiography (B-mode and speckle tracking).
- Infarct size, fibrosis, and inflammation (TNFα) were quantified via histological staining and immunofluorescence.
Main Results:
- PNA5 treatment led to early improvements in ejection fraction and significantly enhanced strain and reduced dyssynchrony.
- Untreated animals exhibited persistent dysfunction in GLS and dyssynchrony, unlike ejection fraction measures.
- PNA5 significantly reduced infarct size and cardiac remodeling, evidenced by decreased scarring in the mid-apical regions.
Conclusions:
- PNA5 demonstrates significant cardioprotective effects, improving cardiac outcomes after IR injury.
- The therapeutic efficacy of PNA5 suggests its potential as a novel treatment for IR injury.
- Measures of GLS and dyssynchrony appear more sensitive than ejection fraction in revealing PNA5's protective benefits.
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