Diabetic Cardiomyopathy: TGFbeta activation and fibrosis

描述（由申请人提供）：糖尿病性心肌病，特征为 肌细胞肥大和间质纤维化，是一种潜在的 由于血糖控制不足而导致的危及生命的并发症。 与糖尿病相关的高血压增加了疾病的严重程度。TGF-β是 高血糖导致纤维化的主要效应物。生物激活 潜伏TGF-β是控制TGF-β的主要调节步骤， 治疗干预的逻辑点。然而，TGF-β的调节 在这些疾病中的生物活性尚不清楚。血小板/基质 血小板反应蛋白1（TSP 1）是一种潜在的血小板活化的生理调节因子， TGF-β激活。TSP 1调节葡萄糖刺激的TGF-β增加 系膜细胞生物活性和基质蛋白合成。TSP依赖 TGF-β激活对糖尿病心肌也很重要，因为高水平的TGF-β激活对糖尿病心肌也很重要。 葡萄糖刺激大鼠心脏成纤维细胞中的TSP 1和TGF-β生物活性， TGF-β生物活性的增加被TSP拮抗肽阻断。 同样，数据显示血管紧张素II（Ang 11）刺激增加TSP 1， 表达和TGF-β生物活性，可以通过添加 拮抗肽。葡萄糖和血管紧张素II均上调TSP 1表达， 可能通过调节PKC和一氧化氮（NO）。这些数据支持 假设葡萄糖介导的PKC、NO、ROS和Ang II的调节是 参与TSP 1表达的调节，导致潜在的TGF-β 活化、基质蛋白合成和心肌纤维化。在这 建议，我们将使用培养的心脏成纤维细胞系统，以确定1） 葡萄糖、PKC活性和氧化平衡之间的相互关系 TSP 1表达、TGF-β生物活性和基质蛋白的调节 2）Ang II在TSP 1依赖性TGF-β调节中的作用 激活及其与葡萄糖刺激的关系。此外， 糖尿病（链脲佐菌素）和高血压糖尿病将用于确定 3)TSP介导的TGF-β活化的肽拮抗剂是否改善了 正常和高血压条件下的糖尿病心肌纤维化。这些 这些研究将使我们进一步了解TGF-β在糖尿病中是如何调节的 和高血压，并可能确定新的战略， 治疗性地减弱心肌纤维化。

DESCRIPTION (provided by applicant): Diabetic cardiomyopathy, characterized by myocyte hypertrophy and interstitial fibrosis, is a potentially life-threatening complication resulting from lack of glycemic control. Hypertension associated with diabetes increases disease severity. TGF-beta is the primary effector of fibrosis in response to hyperglycemia. Bioactivation of latent TGF-beta is a major regulatory step in controlling TGF-beta and a logical point for therapeutic intervention. Yet, regulation of TGF-beta bioactivity in these diseases is not well understood. The platelet/matrix protein, thrombospondin l (TSP 1), is a physiologic regulator of latent TGF-beta activation. TSP 1 regulates glucose-stimulated increases in TGF-beta bioactivity and matrix protein synthesis in mesangial cells. TSP-dependent TGF-beta activation is also important for the diabetic myocardium, since high glucose stimulates TSP1 and TGF-beta bioactivity in rat cardiac fibroblasts and increases in TGF-beta bioactivity are blocked with TSP antagonist peptides. Similarly, data show that angiotensin II (Ang 11)-stimulates increased TSP 1 expression and TGF-beta bioactivity that can be blocked by addition of the antagonist peptides. Both glucose and Ang II up-regulate TSP 1 expression, potentially through modulation of PKC and nitric oxide (NO). These data support the hypothesis that glucose-mediated modulation of PKC, NO, ROS, and Ang II are involved in the regulation of TSP1 expression, leading to latent TGF-beta activation, matrix protein synthesis, and myocardial fibrosis. In this proposal, we will use a cultured cardiac fibroblast system to determine 1) the interrelationships between glucose, PKC activity, and oxidative balance in regulation of TSP 1 expression, TGF-beta bioactivity, and matrix protein synthesis and; 2) the role of Ang II in regulation of TSP 1-dependent TGF-beta activation and its relation to glucose stimulation. In addition, rats with diabetes (streptozotocin) and hypertensive diabetes will be used to determine 3) whether peptide antagonists of TSP-mediated TGF-beta activation ameliorate diabetic myocardial fibrosis under normo- and hypertensive conditions. These studies will further our understanding of how TGF-beta is regulated in diabetes and hypertension, and will potentially identify new strategies for therapeutically attenuating myocardial fibrosis.