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.
Highlights
Treatment of ST-elevation myocardial infarction (MI) focuses on rapidly re-establishing perfusion following blockage in one or more of the epicardial coronary arteries
Immunofluorescence staining of frozen heart sections demonstrated very low constitutive expression of IL-36R in adult sham hearts
The molecular weight of IL-36R is approximately 65kDa, but it migrates to the position of approximately 85kDa in denaturing protein gels [29]
Summary
Treatment of ST-elevation myocardial infarction (MI) focuses on rapidly re-establishing perfusion following blockage in one or more of the epicardial coronary arteries This can be achieved by primary percutaneous coronary interventions (PCI) using a coronary stent to open the culprit artery. Despite these interventions, a substantial proportion of patients still incur extensive muscle damage and develop heart failure post-MI [1]. Restoration of normal epicardial blood vessel flow but with sub-optimal myocardial perfusion, can be observed in up to 50% of patients following PCI, leading to worse outcomes than in patients with full perfusion recovery [2] This suggests tissue damage likely occurs subsequent to inadequate coronary microcirculatory perfusion [3,4]. Current clinical tools cannot resolve microvessels
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