BS13 Intravital investigations of the role of IL-36 in mediating age and gender specific changes in the injured beating coronary microcirculation

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Abstract

Introduction Whilst blood flow restoration is critical following myocardial infarction (MI), ischemia-reperfusion injury (IRI) accounts for ~50% of the final infarct size. We have previously shown intravitally that myocardial IRI induces thromboinflammation and reduces functional capillary density (FCD) in adult mouse beating heart microcirculation in vivo. [1] The newly discovered and inflammatory cytokine, interleukin-36 (IL-36), could potentially mediate these disturbances. However, its role in myocardial IRI is not known. This study aimed to determine whether coronary microcirculatory disturbances and infarct size post-IRI were modified by age and gender. Secondly, we investigated if IL-36 (α/β) and its receptor (IL-36R) were present in the heart, and whether their expression varied in an injury and age-related manner. Lastly, we investigated whether an IL-36 receptor antagonist (IL-36Ra) could confer vasculoprotection and reduce myocardial infarction.

Methods Myocardial IRI was induced in adult (3-months) and aged (>18-months) female mice, with gender differences assessed in adult male and female mice. Beating heart coronary microcirculation was imaged intravitally and also ex vivo using multiphoton microscopy. IL-36R/α/β, and VCAM-1 expression were investigated immunohistochemically or using western blots. In some studies, recombinant mouse IL-36Ra (15ug/mouse) was injected intra-arterially at 5 minutes pre-reperfusion and 60 minutes post-reperfusion. Infarct size was measured using dual TTC/Evans Blue staining.

Results Significantly increased basal (p<0.0001) and IRI-induced (p<0.0001) neutrophil recruitment, and greater decreases in FCD, was observed in aged mice compared to adults. Neutrophils primarily adhered within coronary capillaries although in aged hearts remarkable venular adhesion was also identified. These events were mirrored in deeper myocardial layers when imaged using multiphoton microscopy. Interesting gender-dependent perturbations were noted. Neutrophil recruitment dominated in injured female hearts whilst male hearts demonstrated a greater presence of occlusive platelet microthrombi. IL-36R/α/β were expressed predominantly on vasculature of murine hearts, with cardiomyocyte and intercalated disc expression being observed. Expression of IL-36R/α/β and VCAM-1 significantly increased with injury and age (see table 1). Interestingly, increased injury and age- related vascular expression of IL-36R/α/ß was observed specifically on micro- and not macro-vessels. IL-36Ra significantly reduced inflammation (p<0.0001) and infarct size (p<0.0001) in both adult and aged mice.
Original languageEnglish
Article numberA162
Number of pages1
JournalHeart
Volume107
Issue numberSuppl 1
DOIs
Publication statusPublished - 4 Jun 2021

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