Hamblin Milton, Friedman David B, Hill Salisha, Caprioli Richard M, Smith Holly M, Hill Michael F
Department of Biomedical Sciences, Division of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, USA.
J Mol Cell Cardiol. 2007 Apr;42(4):884-95. doi: 10.1016/j.yjmcc.2006.12.018. Epub 2007 Jan 10.
Diabetic cardiomyopathy has been documented as an underlying etiology of heart failure (HF) among diabetics. Although oxidative stress has been proposed to contribute to diabetic cardiomyopathy, much of the evidence lacks specificity. Furthermore, whether alterations occur at the cardiac proteome level in diabetic cardiac complications with attendant oxidative stress remains unknown. Therefore, we sought to identify cardiac protein changes in relation to myocardial oxidative stress that are specific to diabetic cardiomyopathy. Diabetes was induced in rats by a single injection of streptozotocin (STZ). STZ-treated rats were examined for diabetic cardiomyopathy at 8 weeks post-STZ by left ventricular (LV) hemodynamic analysis. LV systolic pressure (LVSP), rate of pressure rise (+dP/dt), and rate of pressure decay (-dP/dt) were depressed while LV end-diastolic pressure (LVEDP) was increased. Myocardial oxidative stress was increased in STZ-diabetic rats, as indexed by significant increases in myocardial formation of 8-iso PGF(2alpha) and oxidized glutathione (GSSG). In-depth mining of the diabetic myocardial proteome by proteomic analysis utilizing two-dimensional difference gel electrophoresis and mass spectrometry (DIGE/MS) techniques revealed that a high proportion (12 of 24) of the altered proteins that could be identified by mass spectrometry were localized to the mitochondria. Down-regulation of antioxidant and anti-apoptotic proteins was also observed in STZ-diabetic hearts. These results characterize a specific 'type I diabetic' pattern of cardiac proteome changes indicative of diabetic cardiomyopathy presenting with higher oxidative stress, supporting the idea that analysis of isoprostane biosynthesis and protein expression profiles may be useful diagnostically to assess the efficacy of antioxidant therapies as prophylactic treatments against type I diabetes mellitus complications involving the heart.
糖尿病性心肌病已被确认为糖尿病患者心力衰竭（HF）的潜在病因。尽管有人提出氧化应激会导致糖尿病性心肌病，但许多证据缺乏特异性。此外，在伴有氧化应激的糖尿病心脏并发症中，心脏蛋白质组水平是否发生改变仍不清楚。因此，我们试图确定与心肌氧化应激相关的、特定于糖尿病性心肌病的心脏蛋白质变化。通过单次注射链脲佐菌素（STZ）诱导大鼠患糖尿病。在注射STZ后8周，通过左心室（LV）血流动力学分析检查STZ处理的大鼠是否患有糖尿病性心肌病。左心室收缩压（LVSP）、压力上升速率（+dP/dt）和压力衰减速率（-dP/dt）降低，而左心室舒张末期压力（LVEDP）升高。STZ糖尿病大鼠的心肌氧化应激增加，心肌中8-异前列腺素F2α（8-iso PGF2α）和氧化型谷胱甘肽（GSSG）的形成显著增加，这可作为指标。利用二维差异凝胶电泳和质谱（DIGE/MS）技术对糖尿病心肌蛋白质组进行深入挖掘，结果显示，通过质谱鉴定出的改变蛋白中，有很大一部分（24个中的12个）定位于线粒体。在STZ糖尿病心脏中还观察到抗氧化和抗凋亡蛋白的下调。这些结果描绘了一种特定的“1型糖尿病”心脏蛋白质组变化模式，表明糖尿病性心肌病伴有较高的氧化应激，支持这样一种观点，即分析异前列腺素生物合成和蛋白质表达谱可能有助于诊断评估抗氧化疗法作为预防1型糖尿病心脏并发症的疗效。
