Department of Medicine, University of California, San Diego, La Jolla, California 92093-0618, USA.
Am J Physiol Regul Integr Comp Physiol. 2012 Oct 1;303(7):R689-99. doi: 10.1152/ajpregu.00548.2011. Epub 2012 Aug 8.
We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardiographic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca(2+) ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.
我们研究了酶蛋白 O-GlcNAc 化在 2 型糖尿病（DM2）小鼠模型中糖尿病心肌病发展中的作用。注射低剂量链脲佐菌素并喂食高脂肪饮食的小鼠出现轻度高血糖和肥胖，与 DM2 一致。在启动 DM2 方案后 1 至 6 个月进行了研究。1 个月后，DM2 小鼠体重增加，空腹血糖受损，胰岛素血症。超声心动图评估显示，2 个月时左心室舒张功能障碍，数种心脏蛋白和核转录因子 Sp1 的 O-GlcNAc 化。4 个月时观察到收缩功能障碍，肌浆网 Ca2+ATP 酶表达降低 50%。在 DM2 小鼠的任何时间点均未观察到纤维化。己糖胺生物合成途径的限速酶谷氨酰胺：果糖-6-磷酸酰胺转移酶（GFAT）的水平早在 2 个月时就升高了。脂肪酸在 DM2 小鼠中升高，可能与过度的蛋白 O-GlcNAc 化水平有关，因为在正常葡萄糖培养的心肌细胞中，用油酸处理可增加 O-GlcNAc 化和 GFAT 水平。这些数据表明，在没有心脏肥大或纤维化的情况下，舒张功能障碍的早期发作随后是收缩功能丧失，与心脏蛋白 O-GlcNAc 化增加和关键钙处理蛋白的 O-GlcNAc 化水平增加有关。通过 O-GlcNAcase 过表达减少 O-GlcNAc 化可改善糖尿病小鼠的心脏功能，这进一步支持了蛋白 O-GlcNAc 化与心脏功能障碍之间存在联系。此外，脂肪酸在刺激过度的 O-GlcNAc 化中起作用。心脏功能观察到的变化的性质和时间过程表明，蛋白 O-GlcNAc 化在 DM2 中糖尿病心肌病的触发中起机械作用。
