Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes
Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes
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DOI：
10.1210/en.2006-0728
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Boccuzzi, Giuseppe
中科院分区：
文献类型：
--
作者：
Aragno, Manuela;Mastrocola, Raffaella;Boccuzzi, Giuseppe
氧化应激在糖尿病性心肌病的发病机制中起关键作用，糖尿病性心肌病以心肌细胞损失和纤维化为特征，最终导致心力衰竭。该研究观察了氧化应激导致糖尿病大鼠左心室心肌收缩力降低的下游信号，以及在几个实验模型中，脱氢表雄酮（DHEA）的作用，脱氢表雄酮的产生在衰竭的心脏中被抑制，并防止高血糖引起的氧化损伤。对链脲佐菌素（STZ）诱导的糖尿病大鼠和遗传性糖尿病-脂肪（ZDF）大鼠，以4 mg/ d / d的剂量口服脱氢表雄酮（DHEA） 21 d。测定stz -糖尿病大鼠和ZDF大鼠左心室氧化平衡、晚期糖化终产物（AGEs）和AGE受体、心肌生成因子和肌球蛋白重链基因表达。慢性高血糖诱导的氧化应激增加了AGE和AGE受体，并导致多效性转录因子核因子- κ B的激活，核因子- κ B的激活触发了一系列信号传导，最终导致心肌肌球蛋白重链（MHC）基因表达从α -MHC亚型转变为β -MHC亚型。DHEA治疗通过阻止高血糖诱导的氧化通路激活，抵消stz -糖尿病大鼠和ZDF大鼠心脏AGE受体激活增强，使下游信号正常化，从而避免心肌生成因子、心脏自主神经系统和神经嵴衍生物（HAND）和肌生成增强因子-2的损害以及MHC基因表达的转换，这是糖尿病心肌病的早期事件。
Oxidative stress plays a key role in the pathogenesis of diabetic cardiomyopathy, which is characterized by myocyte loss and fibrosis, finally resulting in heart failure. The study looked at the downstream signaling whereby oxidative stress leads to reduced myocardial contractility in the left ventricle of diabetic rats and the effects of dehydroepiandrosterone ( DHEA), which production is suppressed in the failing heart and prevents the oxidative damage induced by hyperglycemia in several experimental models. DHEA was given orally at a dose of 4 mg/rat per day for 21 d to rats with streptozotocin (STZ)-induced diabetes and genetic diabetic-fatty (ZDF) rats. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, cardiac myogenic factors, and myosin heavy-chain gene expression were determined in the left ventricle of treated and untreated STZ-diabetic rats and ZDF rats. Oxidative stress induced by chronic hyperglycemia increased AGE and AGE receptors and led to activation of the pleoitropic transcription factor nuclear factor-kappa B. Nuclear factor-kappa B activation triggered a cascade of signaling, which finally led to the switch in the cardiac myosin heavy-chain (MHC) gene expression from the alpha-MHC isoform to the beta-MHC isoform. DHEA treatment, by preventing the activation of the oxidative pathways induced by hyperglycemia, counteracted the enhanced AGE receptor activation in the heart of STZ-diabetic rats and ZDF rats and normalized downstream signaling, thus avoiding impairment of the cardiac myogenic factors, heart autonomic nervous system and neural crest derivatives (HAND) and myogenic enhancer factor-2, and the switch in MHC gene expression, which are the early events in diabetic cardiomyopathy.