TXNIP: A NOVEL APPROACH TO PREVENT DIABETIC CARDIOMYOPATHY AND HEART FAILURE

TXNIP：预防糖尿病心肌病和心力衰竭的新方法

• 批准号: 7293726
• 负责人: Anath Shalev
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7293726
• 关键词: Apoptosis; Calcium Channel Blockers; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cleaved cell; Collagen; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Echocardiography; Epidemic; Fibrosis; Gene Proteins; Genetic Transcription; Glucose; Heart; Heart failure; Histocytochemistry; Immunoblotting; In Situ Nick-End Labeling; Incubated; Injection of therapeutic agent; Injury; Light; Measurement; Molecular; Mus; Mutation; Myocardial Infarction; Nonsense Mutation; Numbers; Obesity; Oxidation-Reduction; Pathogenesis; Patients; Play; Prevention therapy; Process; Promoter Regions; Protein Deficiency; Protein Overexpression; Proteins; Public Health; Role; Streptozocin; Testing; Thioredoxin; Transcriptional Regulation; Transfection; Verapamil; Wild Type Mouse; base; caspase-3; cis acting element; deletion analysis; diabetic; diabetic cardiomyopathy; gel mobility shift assay; human TXNIP protein; in vivo; insight; knock-down; mouse model; mutant; novel strategies; nutrition; prevent; promoter; protein expression

DESCRIPTION (provided by applicant): Cardiomyopathy and heart failure are potentially fatal complications of diabetes. They also represent a growing public health problem due to the worldwide obesity epidemic, unhealthy nutrition and associated increase in the number of patients with diabetes. However, the molecular mechanisms leading to diabetes-induced cardiomyocyte injury are still not fully understood making the development of protective therapies very difficult. Recently, we found that the redox regulator, thioredoxin-interacting protein (TXNIP) is induced by glucose, that TXNIP overexpression enhances apoptosis and that cardiac TXNIP expression is upregulated in diabetes, suggesting that increased expression of TXNIP may play a role in diabetic cardiomyocyte injury. TXNIP was also found to be increased in cardiomyocytes after myocardial infarction and knock down of TXNIP reduced the associated apoptosis and fibrosis. Surprisingly, we observed that calcium channel blocker lower cardiac expression of TXNIP, as well as of cleaved caspase-3 and collagen in normal mice. The hypothesis is therefore that decreasing TXNIP expression may represent a novel strategy to inhibit diabetes-induced cardiomyocyte damage. The aims are: SPECIFIC AIM 1. Study the effects of calcium channel blocker on diabetes-induced TXNIP expression and apoptosis in heart and elucidate the molecular mechanisms involved. Wild-type mice will be made diabetic by streptozotocin (STZ) injection and the effects of calcium channel blocker on cardiac apoptosis, fibrosis and the expression of TXNIP, cleaved caspase-3 and collagen will be assessed by TUNEL, histochemistry and immuoblotting. Effects on cardiac function will be analyzed by echocardiography. To assess the molecular mechanisms by which calcium channel blocker regulate TXNIP transcription, a detailed promoter analysis will be performed using H9C2 cardiomyocytes. SPECIFIC AIM 2. Assess whether TXNIP-deficient mice are protected against diabetes-induced cardiac alterations. These studies will be facilitated by the availability of a unique mouse model (HcB-19) harboring a natural nonsense mutation in the TXNIP gene. TXNIP-mutant HcB-19 mice will be rendered diabetic with STZ and the effects of TXNIP-deficiency on cardiomyocyte apoptosis, fibrosis and function analyzed as under aim 1. The results of these studies should help define the role of TXNIP in diabetes-induced cardiomyocyte damage, provide insight into the mechanisms involved, and reveal potential treatment strategies directed towards enhancing cardiomyocyte survival and preventing cardiomyopathy and heart failure.

描述（由申请人提供）：心肌病和心力衰竭是糖尿病的潜在致命并发症。由于全球肥胖症的流行，不健康的营养以及糖尿病患者数量的增加，它们也代表了日益增长的公共卫生问题。但是，导致糖尿病引起的心肌细胞损伤的分子机制仍未完全了解，这使得保护性疗法的发展非常困难。最近，我们发现氧化还原调节剂硫蛋白相互作用蛋白（TXNIP）是由葡萄糖诱导的，TXNIP过表达会增强凋亡，并且该心脏TXNIP表达在糖尿病中上调，这表明TXNIP的增加可能在TXNIP的表达中起作用，在糖尿病性心脏瘤造成的表达中可能起作用。在心肌梗塞后心肌细胞中还发现TXNIP增加了TXNIP，而TXNIP降低了TXNIP可减少相关的凋亡和纤维化。令人惊讶的是，我们观察到钙通道阻滞剂在正常小鼠中的钙通道阻滞剂较低的心脏表达以及裂解的caspase-3和胶原蛋白。因此，假设降低TXNIP表达可能代表了抑制糖尿病诱导的心肌细胞损伤的新型策略。目的是：特定目标1。研究钙通道阻滞剂对心脏中糖尿病诱导的TXNIP表达和凋亡的影响，并阐明所涉及的分子机制。野生型小鼠将通过链蛋白酶（STZ）注射和钙通道阻滞剂对心脏凋亡，纤维化和TXNIP，裂解caspase-3和胶原蛋白的表达的影响使野生型小鼠进行糖尿病。对心脏功能的影响将通过超声心动图分析。为了评估钙通道阻滞剂调节TXNIP转录的分子机制，将使用H9C2心肌细胞进行详细的启动子分析。具体目标2。评估缺乏TXNIP的小鼠是否受到糖尿病诱导的心脏改变的保护。这些研究将通过在TXNIP基因中具有天然废话突变的独特小鼠模型（HCB-19）的可用性来促进。 TXNIP-突出的HCB-19小鼠将与STZ培养糖尿病，以及TXNIP缺乏对心肌细胞凋亡，纤维化，纤维化和功能的影响。这些研究的结果应有助于定义TXNIP在糖尿病诱导的型型心疗法损害中的作用，并揭示了疾病的疾病，并揭示了对糖尿病的策略，并提供了良好的机制，并启发了洞察力，并有助于确定的机制，并有助于确定的机制，并有助于确定良好的机制，并确定洞察力的作用。心肌细胞的存活和预防心肌病和心力衰竭。