Hydrogel delivery of purinergic enzymes improves cardiac ischemia/reperfusion injury.

Autor: Sayegh MN; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States of America; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States of America., Cooney KA; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States of America; Department of Biological Sciences, Tennessee State University, Nashville, TN, United States of America., Han WM; Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States of America; Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Cicka M; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States of America., Strobel F; Department of Chemistry, Emory University, Atlanta, GA, United States of America., Wang L; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States of America., García AJ; Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States of America., Levit RD; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States of America; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States of America. Electronic address: rlevit@emory.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2023 Mar; Vol. 176, pp. 98-109. Date of Electronic Publication: 2023 Feb 09.
DOI: 10.1016/j.yjmcc.2023.02.001
Abstrakt: Rationale: The innate immune response contributes to cardiac injury in myocardial ischemia/reperfusion (MI/R). Neutrophils are an important early part of the innate immune response to MI/R. Adenosine, an endogenous purine, is a known innate immune modulator and inhibitor of neutrophil activation. However, its delivery to the heart is limited by its short half-life (<30 s) and off-target side effects. CD39 and CD73 are anti-inflammatory homeostatic enzymes that can generate adenosine from phosphorylated adenosine substrate such as ATP released from injured tissue.
Objective: We hypothesize that hydrogel-delivered CD39 and CD73 target the local early innate immune response, reduce neutrophil activation, and preserve cardiac function in MI/R injury.
Methods and Results: We engineered a poly(ethylene) glycol (PEG) hydrogel loaded with the adenosine-generating enzymes CD39 and CD73. We incubated the hydrogels with neutrophils in vitro and showed a reduction in hydrogen peroxide production using Amplex Red. We demonstrated availability of substrate for the enzymes in the myocardium in MI/R by LC/MS, and tested release kinetics from the hydrogel. On echocardiography, global longitudinal strain (GLS) was preserved in MI/R hearts treated with the loaded hydrogel. Delivery of purinergic enzymes via this synthetic hydrogel resulted in lower innate immune infiltration into the myocardium post-MI/R, decreased markers of macrophage and neutrophil activation (NETosis), and decreased leukocyte-platelet complexes in circulation.
Conclusions: In a rat model of MI/R injury, CD39 and CD73 delivered via a hydrogel preserve cardiac function by modulating the innate immune response.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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