Role and mechanism of connective tissue growth factor in diabetic cardiomyopathy

结缔组织生长因子在糖尿病心肌病中的作用及机制

• 批准号: nhmrc : 402559
• 负责人: A/Pr Susan Mclennan
• 金额: $ 25.53万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-mechanism-connective-diabetic-cardiomyopathy/77064
• 关键词: Role; mechanism; connective; tissue; growth

Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen patient outcomes. We have generated data in experimental diabetes in rodents that strongly implicates a heart growth factor in causing diabetic cardiomyopathy. This protein, called connective tissue growth factor (CTGF), is increased in diabetic cardiomyopathy, and is elevated by high glucose and other factors in diabetes. We have published data showing that CTGF causes tissue scarring like that which occurs in cardiomyopathy, by affecting signals in cells called fibroblasts. It increases the laying down of extracellular matrix (ECM) and also inhibits the degradation of ECM by the proteins that break down matrix, known as the MMPand PAI systems. Such accumulation of ECM is thought to be a major factor leading to abnormal muscle function in cardiomyopathy. We now plan to block CTGF in this diabetic heart model to determine if we can prevent diabetic cardiomyopathy. We have generated two methods to inhibit CTGF in the animal model. Echocardiography (a heart ultrasound test), and molecular analysis of the heart tissue will determine if we can prevent the otherwise adverse functional and structural changes of diabetes in the heart. We will also study our baboon model of diabetes to determine if diabetic cardiomyopathy with increased heart CTGF is present in the primates. Cell culture studies from rat heart fibroblasts and myocytes will determine how CTGF has the effect on cells to cause cardiomyopathy and how we might further prevent this condition developing in diabetes.

糖尿病性心肌病是一种由糖尿病直接损害心肌的疾病。它被认为是糖尿病急性和慢性心力衰竭的主要原因。这是常见的，发生在高达60%的糖尿病患者。然而，目前还没有直接治疗心肌病的治疗方法。这种情况也可能发生在患有高血压和/或冠状动脉疾病的糖尿病患者中，并可能与这些问题联合收割机结合，使患者的预后恶化。我们在啮齿动物实验性糖尿病中获得的数据强烈暗示心脏生长因子导致糖尿病性心肌病。这种蛋白质，称为结缔组织生长因子（CTGF），在糖尿病心肌病中增加，并在糖尿病中因高糖和其他因素而升高。我们已经发表的数据表明，CTGF通过影响称为成纤维细胞的细胞中的信号，导致组织瘢痕形成，就像心肌病中发生的那样。它增加了细胞外基质（ECM）的沉积，也抑制了ECM被称为MMP和派系统的分解基质的蛋白质降解。ECM的这种积累被认为是导致心肌病中肌肉功能异常的主要因素。我们现在计划在这个糖尿病心脏模型中阻断CTGF，以确定我们是否可以预防糖尿病心肌病。我们已经产生了两种方法来抑制CTGF的动物模型。超声心动图（心脏超声检查）和心脏组织的分子分析将确定我们是否可以预防糖尿病在心脏中的其他不良功能和结构变化。我们还将研究我们的糖尿病狒狒模型，以确定是否有心脏CTGF增加的糖尿病心肌病存在于灵长类动物中。对大鼠心脏成纤维细胞和肌细胞的细胞培养研究将确定CTGF如何影响细胞引起心肌病，以及我们如何进一步预防糖尿病中的这种情况。