Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, UK.
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
J Physiol. 2019 Sep;597(17):4481-4501. doi: 10.1113/JP278332. Epub 2019 Jul 26.
Acute hyperglycaemia at the time of a heart attack worsens the outcome for the patient. Acute hyperglycaemia is not limited to diabetic patients and can be due to a stress response in non-diabetics. This study suggests that the damaging cardiac effects of hyperglycaemia can be reversed by selective PKC inhibition. If PKCα/β isoforms are inhibited, then high glucose itself becomes protective against ischaemic damage. Selective PKC inhibition may therefore be a useful therapeutic tool to limit the damage that can occur during a heart attack by stress-induced hyperglycaemia.
Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows that high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via protein kinase C α/β (PKCα/β) activation. The present study aimed to: (i) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS and (ii) determine the importance of PKCα/β activation to the deleterious effect of glucose. Freshly isolated rat, guinea pig or rabbit cardiomyocytes were exposed to simulated ischaemia after incubation in the presence of normal (5 mm) or high (20 mm) glucose in the absence or presence of small molecule or tat-peptide-linked PKCαβ inhibitors. In each of the four conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescence imaging: cardiomyocyte contraction and survival, action potential stability and time to failure, intracellular calcium and ATP, mitochondrial depolarization, ischaemia-sensitive leak current, and time to K 6.2 opening. High glucose alone resulted in decreased cardiomyocyte contraction and survival; however, it also imparted cardioprotection in the presence of PKCα/β inhibitors. This cardioprotective phenotype displayed improvements in all of the measured parameters and decreased myocardium damage during whole heart coronary ligation experiments. High glucose is deleterious to cellular and whole-heart models of simulated ischaemia, in keeping with the clinical association of hyperglycaemia with an adverse outcome in ACS. PKCαβ inhibition revealed high glucose to show a cardioprotective phenotype in this setting. The results of the present study suggest the potential for the therapeutic application of PKCαβ inhibition in ACS associated with hyperglycaemia.
急性心肌梗时的高血糖会使患者的预后恶化。急性高血糖不仅限于糖尿病患者，也可能是由于非糖尿病患者的应激反应引起的。这项研究表明，选择性蛋白激酶 C（PKC）抑制可以逆转高血糖对心脏的损害作用。如果抑制 PKCα/β同工型，那么高葡萄糖本身就可以防止缺血损伤。因此，选择性 PKC 抑制可能是一种有用的治疗工具，可以通过应激诱导的高血糖限制心肌梗时发生的损伤。
高血糖与急性冠状动脉综合征（ACS）患者的不良预后密切相关。先前的研究表明，高葡萄糖通过蛋白激酶 Cα/β（PKCα/β）的激活来阻止缺血预处理并导致电和机械功能障碍。本研究旨在：（i）在 ACS 的临床前细胞模型中复制 ACS 中高血糖的不良临床相关性；（ii）确定 PKCα/β激活对葡萄糖的有害影响的重要性。在不存在或存在小分子或 tat 肽连接的 PKCαβ抑制剂的情况下，将新鲜分离的大鼠、豚鼠或兔心肌细胞在正常（5mm）或高（20mm）葡萄糖孵育后暴露于模拟缺血。在这四种情况下，使用电生理学或荧光成像记录以下心脏保护的特征：心肌细胞收缩和存活、动作电位稳定性和衰竭时间、细胞内钙和 ATP、线粒体去极化、缺血敏感漏电流以及 K6.2 开放时间。高葡萄糖本身可导致心肌细胞收缩和存活减少；然而，当存在 PKCα/β抑制剂时，它也可提供心脏保护。这种心脏保护表型显示所有测量参数的改善，并在整个心脏冠状动脉结扎实验中减少心肌损伤。高葡萄糖对模拟缺血的细胞和全心脏模型是有害的，这与 ACS 中高血糖与不良预后的临床相关性一致。PKCα/β 抑制揭示了在这种情况下高葡萄糖具有心脏保护表型。本研究的结果表明，PKCα/β 抑制在 ACS 合并高血糖的治疗应用中具有潜力。
