Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
J Mol Cell Cardiol. 2013 Nov;64:20-9. doi: 10.1016/j.yjmcc.2013.08.005. Epub 2013 Aug 30.
It is believed that the diabetic myocardium is refractory to cardioprotection by ischemic preconditioning (IPC) mainly because of impaired insulin signaling to phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB or Akt). However, human as well as animal studies have clearly showed that the hearts of type 2 diabetic humans and animals may exhibit increased signaling through PI3K-Akt but yet are resistant to cardioprotection by IPC or ischemic post-conditioning. Therefore, this study was designed to determine whether activation of insulin signaling prior to IPC is detrimental for cardioprotection and to assess the role of insulin receptors (IRs) and Akt in mediating this effect. Wild-type (WT) hearts, hearts lacking IRs or hearts expressing an active form of Akt (myrAkt1) were perfused ex vivo using a Langendorff preparation and were subjected to IPC (3cycles of 5min ischemia followed by 5min reflow before 30min no flow ischemia and then by 45min reperfusion) in the presence or absence of 1nmol/L insulin. Interestingly, whereas insulin was protective against I/R (30min no flow ischemia and 45min reperfusion), it completely abolished cardioprotection by IPC in WT hearts but not in mice lacking insulin receptors (IRs) in cardiomyocytes (CIRKO) or in all cardiac cells (TIRKO). The suppression of IPC-mediated cardioprotection was mediated through downstream signaling to Akt and Gsk3β. In addition, transgenic induction of Akt in the heart was sufficient to abrogate IPC even when insulin was absent, further confirming the involvement of Akt in insulin's suppression of cardioprotection by IPC. These data provide evidence that excessive insulin signaling to Akt is detrimental for cardioprotection by IPC and could explain the failure of the diabetic myocardium to precondition.
据信，糖尿病心肌对缺血预处理（IPC）的心肌保护作用具有抗性，主要是因为胰岛素信号转导至磷脂酰肌醇 3-激酶（PI3K）和蛋白激酶 B（PKB 或 Akt）受损。然而，人体和动物研究清楚地表明，2 型糖尿病患者和动物的心脏可能表现出 PI3K-Akt 信号的增强，但对 IPC 或缺血后处理的心肌保护作用具有抗性。因此，本研究旨在确定 IPC 前激活胰岛素信号是否对心肌保护有害，并评估胰岛素受体（IRs）和 Akt 在介导这种作用中的作用。使用 Langendorff 制剂对野生型（WT）心脏、缺乏 IRs 的心脏或表达 Akt 的活性形式（myrAkt1）的心脏进行离体灌流，并在存在或不存在 1nmol/L 胰岛素的情况下进行 IPC（3 个周期的 5min 缺血，然后 5min 再灌注，然后 30min 无血流缺血，然后 45min 再灌注）。有趣的是，尽管胰岛素对 I/R（30min 无血流缺血和 45min 再灌注）具有保护作用，但它完全消除了 WT 心脏中 IPC 的心肌保护作用，但在缺乏心肌细胞（CIRKO）或所有心脏细胞（TIRKO）中胰岛素受体（IRs）的小鼠中则不然。IPC 介导的心肌保护作用的抑制是通过 Akt 和 Gsk3β的下游信号转导介导的。此外，心脏中 Akt 的转基因诱导足以消除 IPC，即使没有胰岛素，进一步证实了 Akt 在胰岛素抑制 IPC 介导的心肌保护作用中的参与。这些数据提供了证据表明，Akt 的过度胰岛素信号转导对 IPC 的心肌保护作用有害，并可能解释了糖尿病心肌不能进行预处理的原因。
