Hydrogel delivery of purinergic enzymes improves cardiac ischemia/reperfusion injury

Michael N. Sayegh, Kimberly A. Cooney, Woojin M. Han, Markus Cicka, Frederick Strobel, Lanfang Wang, Andrés J. García, Rebecca D. Levit

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)98-109
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
StatePublished - Mar 2023


  • Adenosine
  • Heart failure
  • Inflammation
  • Ischemia
  • Myocardial infarction


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