Diabetic Cardiomyopathy: TGFbeta activation and fibrosis

描述(申请人提供)：糖尿病心肌病，特征为 心肌细胞肥大和间质纤维化，是一种潜在的 由于缺乏血糖控制而导致的危及生命的并发症。 与糖尿病相关的高血压会增加疾病的严重程度。转化生长因子-β是 高血糖引起的纤维化的主要影响因素。生物活化法 潜伏的转化生长因子-β是控制转化生长因子-β和转化生长因子的主要调控步骤 治疗干预的合乎逻辑的要点。然而，对转化生长因子-β的调控 这些疾病中的生物活性还不是很清楚。血小板/基质 凝血酶原蛋白L(TSP1)是潜伏期的一种生理调节蛋白 转化生长因子-β的激活。TSP-1调节葡萄糖刺激的转化生长因子-β的升高 系膜细胞的生物活性和基质蛋白合成。依赖于TSP 转化生长因子-β的激活对糖尿病心肌也很重要，因为 葡萄糖刺激大鼠心脏成纤维细胞TSP1和转化生长因子-β的生物活性 TSP拮抗剂多肽可阻断转化生长因子-β生物活性的增加。 同样，数据显示血管紧张素II(Ang 11)-刺激TSP1增加 表达和转化生长因子-β生物活性可通过添加 拮抗肽。葡萄糖和血管紧张素Ⅱ均上调TSP-1的表达， 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TSP1表达的调节，导致潜伏的转化生长因子-β 激活、基质蛋白合成与心肌纤维化。在这 建议，我们将使用培养的心脏成纤维细胞系统来确定1) 血糖、PKC活性和氧化平衡之间的相互关系 TSP-1表达、转化生长因子-β生物活性和基质蛋白的调节 合成；2)Ang II在调节依赖TSP 1的转化生长因子-β中的作用 激活及其与葡萄糖刺激的关系。此外，老鼠有 糖尿病(链脲佐菌素)和高血压糖尿病将被用来确定 3)TSP介导的转化生长因子-β活化的多肽拮抗剂是否改善 正常和高血压条件下的糖尿病心肌纤维化。这些 研究将进一步加深我们对转化生长因子-β在糖尿病中的调节方式的理解 和高血压，并可能确定新的治疗策略 从治疗上减轻心肌纤维化。

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.