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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 4

Intravital imaging of the mouse beating heart microcirculation in vivo and multiphoton imaging of the heart ex vivo.

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Intravital imaging of the mouse beating heart microcirculation in vivo a...
(A–C) An in-house–designed 3D-printed stabilizer is lowered onto the beating left ventricle, allowing confocal intravital imaging in its center. Only a small surface of the beating heart has its motion reduced enough to permit imaging. (D) No BP/heart rate changes were detected using this approach as determined by photoplethysmography in both adult and aged sham and IR-injured mice. The graph presented shows BP, which remains constant even after the stabilizer is attached. (E) To ascertain whether any thromboinflammatory and vasculoprotective events imaged intravitally on the surface of the heart were also occurring in the deeper layers of the myocardium, multiphoton microscopy was used. The heart was cut in half longitudinally from the base to apex to expose the inner endocardial layer lining the left ventricle chamber. It was then placed on a specimen holder and attached to a tissue vibratome to precisely section the left ventricle wall into 4 × 300 μm thickness sections from the outermost layer closest to the epicardium, through to the inner layer closest to the endocardium. (F) Multiphoton Z-stacks were taken from all 4 layers, namely the (i) outermost layer closest to the epicardium — epi-to-mid (ii) outer myocardial layer — mid-to-mid (iii) inner myocardial layer — mid-to-mid, and (iv) innermost layer closest to the endocardium — mid-to-endo, avoiding the last section if it had “missing” myocardium due to sectioning through the actual ventricle chamber. Images from each layer were then rendered to form 3D stack images.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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