Brennan Sean, Esposito Simona, Abdelaziz Muhammad I M, Martin Christopher A, Makwana Samir, Sims Mark W, Squire Iain B, Sharma Parveen, Chadwick Amy E, Rainbow Richard D
Department of Cardiovascular, Metabolic Medicine and Liverpool Centre for Cardiovascular Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.
Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, United Kingdom.
Front Cardiovasc Med. 2022 Sep 7;9:997013. doi: 10.3389/fcvm.2022.997013. eCollection 2022.
Hyperglycaemia at the time of myocardial infarction has an adverse effect on prognosis irrespective of a prior diagnosis of diabetes, suggesting glucose is the damaging factor. In models of ischaemia, we demonstrated that deleterious effects of acutely elevated glucose are PKCα/β-dependent, and providing PKCα/β are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/β inhibition investigated as a potential mechanism to reverse the toxicity. Freshly isolated non-diabetic rat cardiomyocytes were exposed to elevated glucose to investigate the time-dependence toxic effects. High glucose challenge for >7.5 min was cardiotoxic, proarrhythmic and lead to contractile failure, whilst cardiomyocytes exposed to metabolic inhibition following 5-min high glucose, displayed a time-dependent protection lasting ∼15 min. This protection was further enhanced with PKCα/β inhibition. Cardioprotection was measured as a delay in contractile failure and K channel activation, improved contractile and Ca transient recovery and increased cell survival. Finally, the effects of pre-ischaemic treatment with high glucose in a whole-heart coronary ligation protocol, where protection was evident with PKCα/β inhibition. Selective PKCα/β inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.
心肌梗死时的高血糖对预后有不利影响，无论之前是否诊断为糖尿病，这表明葡萄糖是造成损害的因素。在缺血模型中，我们证明急性升高的葡萄糖的有害作用是PKCα/β依赖性的，并且如果PKCα/β受到抑制，升高的葡萄糖可提供心脏保护作用。用高糖进行短期预处理以研究时间依赖性的葡萄糖心脏毒性，并研究抑制PKCα/β作为逆转毒性的潜在机制。将新鲜分离的非糖尿病大鼠心肌细胞暴露于升高的葡萄糖中以研究时间依赖性毒性作用。高糖刺激超过7.5分钟具有心脏毒性、促心律失常作用并导致收缩功能衰竭，而在5分钟高糖后暴露于代谢抑制的心肌细胞表现出持续约15分钟的时间依赖性保护作用。PKCα/β抑制可进一步增强这种保护作用。心脏保护作用通过收缩功能衰竭延迟和钾通道激活、收缩和钙瞬变恢复改善以及细胞存活率增加来衡量。最后，在全心冠状动脉结扎方案中，高糖缺血预处理的效果在PKCα/β抑制时明显。选择性PKCα/β抑制增强了保护作用，提示通过抑制PKC进行血糖控制作为心肌梗死和择期心脏手术中潜在的心脏保护治疗方法。
