Impact of chronic hyperglycaemia on the coronary microcirculation – benefits of targeting IL-36 and diet reversal

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Juma El-Awaisi, Dean Kavanagh, Silke Heising, Ina Maria Schiessl, Simon J. Cleary, David J. Hodson, Neena Kalia
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引用次数: 0

Abstract

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.

慢性高血糖对冠状动脉微循环的影响——靶向IL-36和饮食逆转的益处
心肌梗死(MI)后,2型糖尿病(T2DM)患者预后较差,这可能与冠状动脉微血管损伤易感性增加有关。白细胞介素-36 (IL-36)可能介导这种损伤,但其在慢性高血糖损伤心脏微循环中的作用尚不清楚。麻醉小鼠心脏跳动的活体和激光散斑成像评估了16周高脂肪饮食(HFD)诱导的高血糖±心肌缺血再灌注损伤(IR)对冠状动脉微血管的影响。评估中性粒细胞/血小板募集、中性粒细胞胞外陷阱形成、细胞坏死、血管渗漏、血管色调改变、功能性毛细血管密度、心室总灌注和循环炎性细胞因子水平,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,研究了受损HFD小鼠微血管损伤升高是永久性的还是可逆性的。评估的微循环事件在HFD小鼠中基本受到干扰,在损伤后进一步受到干扰。IL-36Ra减轻了这些影响并改善了梗死面积。DR也是有益的,将中性粒细胞募集减少到低于未治疗小鼠的水平。从机制上讲,IL-36Ra和DR的益处可以通过降低内皮氧化应激和VCAM-1表达以及可能通过提高IL-4/IL-13水平来解释。慢性高血糖冠状动脉微血管的基础变化在再灌注后升高,这可能解释了心肌梗死合并T2DM患者预后较差的原因。这些发现首次强调了在临床前T2DM模型中抑制IL-36和通过饮食改变逆转高血糖对冠状动脉微循环的特定益处。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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