Department of Cardiology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, Aarhus N DK-8200, Denmark.
Cardiovasc Res. 2013 Feb 1;97(2):369-78. doi: 10.1093/cvr/cvs337. Epub 2012 Dec 1.
Post-translational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is cardioprotective but its role in cardioprotection by remote ischaemic preconditioning (rIPC) and the reduced efficacy of rIPC in type 2 diabetes mellitus is unknown. In this study we achieved mechanistic insight into the remote stimulus mediating and the target organ response eliciting the cardioprotective effect by rIPC in non-diabetic and diabetic myocardium and the influence of O-GlcNAcylation.
The cardioprotective capacity and the influence on myocardial O-GlcNAc levels of plasma dialysate from eight healthy volunteers and eight type 2 diabetic patients drawn before and after subjection to an rIPC stimulus were tested on human isolated atrial trabeculae subjected to ischaemia/reperfusion injury. Dialysate from healthy volunteers exposed to rIPC improved post-ischaemic haemodynamic recovery (40 ± 6 vs. 16 ± 2%; P < 0.01) and increased myocardial O-GlcNAc levels. Similar observations were made with dialysate from diabetic patients before exposure to rIPC (43 ± 3 vs. 16 ± 2%; P < 0.001) but no additional cardioprotection or further increase in O-GlcNAc levels was achieved by perfusion with dialysate after exposure to rIPC (44 ± 4 and 42 ± 5 vs. 43 ± 3%; P = 0.7). The glutamine:fructose-6-phosphate amidotransferase (GFAT) inhibitor azaserine abolished the cardioprotective effects and the increment in myocardial O-GlcNAc levels afforded by plasma from diabetic patients and healthy volunteers treated with rIPC.
rIPC and diabetes mellitus per se influence myocardial O-GlcNAc levels through circulating humoral factors. O-GlcNAc signalling participates in mediating rIPC-induced cardioprotection and maintaining a state of inherent chronic activation of cardioprotection in diabetic myocardium, restricting it from further protection by rIPC.
蛋白质的 O-连接 β-N-乙酰氨基葡萄糖（O-GlcNAc）的翻译后修饰具有心脏保护作用，但在远程缺血预处理（rIPC）的心脏保护作用及其在 2 型糖尿病中的疗效降低中的作用尚不清楚。在这项研究中，我们深入了解了 rIPC 在非糖尿病和糖尿病心肌中介导远程刺激和引发心脏保护作用的机制，以及 O-GlcNAc 化的影响。
在经历 rIPC 刺激前后，从 8 名健康志愿者和 8 名 2 型糖尿病患者中提取的血浆透析液的心脏保护能力及其对心肌 O-GlcNAc 水平的影响，在经历缺血/再灌注损伤的人离体心房肌中进行了测试。来自健康志愿者的 rIPC 暴露后的透析液改善了缺血后的血流动力学恢复（40±6%比 16±2%；P<0.01）并增加了心肌 O-GlcNAc 水平。糖尿病患者在接受 rIPC 暴露前的透析液也观察到类似的结果（43±3%比 16±2%；P<0.001），但 rIPC 暴露后的透析液灌注并未进一步增加 O-GlcNAc 水平或提供额外的心脏保护作用（44±4%和 42±5%比 43±3%；P=0.7）。谷氨酰胺：果糖-6-磷酸酰胺转移酶（GFAT）抑制剂氨唑西林消除了来自糖尿病患者和接受 rIPC 治疗的健康志愿者的血浆所带来的心脏保护作用和心肌 O-GlcNAc 水平的增加。
rIPC 和糖尿病本身通过循环体液因子影响心肌 O-GlcNAc 水平。O-GlcNAc 信号参与介导 rIPC 诱导的心脏保护作用，并维持糖尿病心肌固有慢性心脏保护作用的激活状态，限制其进一步受 rIPC 保护。
