El-Awaisi Juma, Kavanagh Dean, Heising Silke, Schiessl Ina Maria, Cleary Simon J, Hodson David J, Kalia Neena
Microcirculation Research Group, Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2 TT, UK.
Department of Metabolism and Systems Research, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2 TT, UK.
Basic Res Cardiol. 2025 Apr 17. doi: 10.1007/s00395-025-01107-y.
Following myocardial infarction (MI), patients with type 2 diabetes mellitus (T2DM) have poorer prognosis which may be linked to increased susceptibility of coronary microvessels to injury. Interleukin-36 (IL-36) may mediate this injury but its role in the microcirculation of the chronically hyperglycaemic injured heart is unknown. Intravital and laser speckle imaging of the anaesthetised mouse beating heart evaluated the impact of a 16-week high fat diet (HFD)-induced hyperglycaemia ± myocardial ischaemia-reperfusion injury (IR) injury on coronary microvessels. Neutrophil/platelet recruitment, neutrophil extracellular trap formation, cellular necrosis, vascular leakage, vascular tonal changes, functional capillary density, overall ventricular perfusion and levels of circulating inflammatory cytokines were assessed alongside the vasculoprotective ability of an IL-36 receptor antagonist (IL-36Ra). Whether heightened microvessel damage in injured HFD mice was permanent or reversible was investigated after normalising hyperglycaemia through diet reversal (DR). Microcirculatory events assessed were perturbed basally in HFD mice and further after injury. IL-36Ra mitigated these effects and improved infarct size. DR was also beneficial, decreasing neutrophil recruitment to levels below those seen in untreated mice. Mechanistically, benefits of both IL-36Ra and DR could be explained by decreased endothelial oxidative stress and VCAM-1 expression and possibly by raised levels of IL-4/IL-13. Basal changes in chronically hyperglycaemic coronary microvessels that are heightened in the aftermath of reperfusion may explain the poorer outcomes in MI patients with T2DM. These findings are the first to highlight the specific benefits of IL-36 inhibition and reversing hyperglycaemia through dietary modification on the coronary microcirculation in a preclinical model of T2DM.
心肌梗死（MI）后，2型糖尿病（T2DM）患者的预后较差，这可能与冠状微血管对损伤的易感性增加有关。白细胞介素-36（IL-36）可能介导这种损伤，但其在长期高血糖损伤心脏微循环中的作用尚不清楚。对麻醉的小鼠跳动心脏进行活体和激光散斑成像，评估了16周高脂饮食（HFD）诱导的高血糖±心肌缺血再灌注损伤（IR）对冠状微血管的影响。同时评估了中性粒细胞/血小板募集、中性粒细胞胞外陷阱形成、细胞坏死、血管渗漏、血管张力变化、功能性毛细血管密度、全心室灌注以及循环炎症细胞因子水平，以及IL-36受体拮抗剂（IL-36Ra）的血管保护能力。在通过饮食逆转（DR）使高血糖正常化后，研究了HFD损伤小鼠微血管损伤加剧是永久性的还是可逆的。评估的微循环事件在HFD小鼠中基础状态下就受到干扰，损伤后进一步加重。IL-36Ra减轻了这些影响并改善了梗死面积。DR也有益处，将中性粒细胞募集减少到未治疗小鼠以下的水平。从机制上讲，IL-36Ra和DR的益处可以通过内皮氧化应激和VCAM-1表达的降低以及可能通过IL-4/IL-13水平的升高来解释。慢性高血糖冠状微血管的基础变化在再灌注后加剧，这可能解释了T2DM心肌梗死患者较差的预后。这些发现首次突出了在T2DM临床前模型中，抑制IL-36和通过饮食调整逆转高血糖对冠状微循环的特定益处。
