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Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischemia/reperfusion injury in mice
Juma El-Awaisi, … , Nigel E. Drury, Neena Kalia
Juma El-Awaisi, … , Nigel E. Drury, Neena Kalia
Published February 3, 2022
Citation Information: JCI Insight. 2022;7(5):e155236. https://doi.org/10.1172/jci.insight.155236.
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Research Article Aging Inflammation

Targeting IL-36 improves age-related coronary microcirculatory dysfunction and attenuates myocardial ischemia/reperfusion injury in mice

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Abstract

Following myocardial infarction (MI), elderly patients have a poorer prognosis than younger patients, which may be linked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), a newly discovered proinflammatory member of the IL-1 superfamily, may mediate this injury, but its role in the injured heart is currently not known. We first demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischemia/reperfusion-injured (IR-injured) mouse hearts and, interestingly, noted that expression of both increased with aging. An intravital model for imaging the adult and aged IR-injured beating heart in real time in vivo was used to demonstrate heightened basal and injury-induced neutrophil recruitment, and poorer blood flow, in the aged coronary microcirculation when compared with adult hearts. An IL-36R antagonist (IL-36Ra) decreased neutrophil recruitment, improved blood flow, and reduced infarct size in both adult and aged mice. This may be mechanistically explained by attenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra–treated mice. Our findings of an enhanced age-related coronary microcirculatory dysfunction in reperfused hearts may explain the poorer outcomes in elderly patients following MI. Since targeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly population.

Authors

Juma El-Awaisi, Dean P.J. Kavanagh, Marco R. Rink, Chris J. Weston, Nigel E. Drury, Neena Kalia

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Figure 9

IL-36R inhibition reduces endothelial and cardiomyocyte oxidative damage and VCAM-1 expression in the IR-injured adult and aged hearts.

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IL-36R inhibition reduces endothelial and cardiomyocyte oxidative damage...
Hearts from adult and aged sham, IR-injured, and IR-injured + IL-36Ra mice were either collagenase digested and analyzed flow cytometrically or sectioned and analyzed using immunofluorescence for oxidative damage and/or VCAM-1 expression. Flow cytometry analysis demonstrated that IR injury increased oxidative damage of both (A) adult and aged coronary endothelial cells and (B) adult and aged cardiomyocytes when compared with appropriate age sham cells. This was reduced in both cell populations in adult and aged mice treated with the IL-36Ra. n = 3/group. (C) Representative immunofluorescence images of CD31 (red) costained with DNA/RNA oxidative damage (green) and VCAM-1 (blue) in sham, IR-injured, and IL-36Ra–treated adult and aged mice. Quantitative analysis of the immunofluorescence images for myocardial (D) oxidative damage and (E) VCAM-1 expression. Scale bar indicates 200 μm. n = 4/group. *P < 0.05, **P < 0.01, ***P < 0.001 as determined using a 1-way ANOVA followed by a Tukey’s post hoc test.

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