A thrombospondin-1 antagonist of transforming growth factor-β activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II
A thrombospondin-1 antagonist of transforming growth factor-β activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II
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DOI：
10.2353/ajpath.2007.070056
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发表时间：
2007-09-01
影响因子：
6
通讯作者：
Berecek, Kathleen H.
中科院分区：
文献类型：
--
作者：
Belmadani, Souad;Bernal, Juan;Berecek, Kathleen H.
在糖尿病和高血压中，由于葡萄糖和血管紧张素H引起的转化生长因子-β（TGF-β）活性增加的诱导是纤维化和器官衰竭发展的重要因素。我们先前表明，葡萄糖和血管紧张素II诱导潜在的TGF-β激活剂血小板反应蛋白-1（TSP 1）。由于潜在的TGF-β激活是调节TGF-β的主要手段，我们使用TSP 1依赖性TGF-β激活的肽拮抗剂，在I型糖尿病大鼠模型中，探讨了TSP 1介导的TGF-β激活在腹主动脉缩窄加重的糖尿病心肌病发展中的作用。这种手术操作提高了初始血压和血管紧张素H。这些大鼠的心脏增加了TSP 1，胶原蛋白和TGF-β的活性，心脏功能减弱。TSPI依赖性TGF-β激活的肽拮抗剂通过降低TGF-β活性防止心脏纤维化的进展并改善心脏功能。这些数据表明TSPI是与刺激肾素-血管紧张素系统相关的糖尿病纤维化并发症的重要介质，并且需要进一步研究来评估TSPI依赖性TGF-β激活的阻断作为潜在的抗纤维化治疗策略。
In diabetes and hypertension, the induction of increased transforming growth factor-beta (TGF-beta) activity due to glucose and angiotensin H is a significant factor in the development of fibrosis and organ failure. We showed previously that glucose and angiotensin II induce the latent TGF-beta activator thrombospondin-1 (TSP1) Because activation of latent TGF-beta is a major means of regulating TGF-beta, we addressed the role of TSPl-mediated TGF-beta activation in the development of diabetic cardiomyopathy exacerbated by abdominal aortic coarctation in a rat model of type I diabetes using a peptide antagonist of TSPI-dependent TGF-beta activation. This surgical manipulation elevates initial blood pressure and angiotensin H. The hearts of these rats had increased TSP1, collagen, and TGF-beta activity, and cardiac function was diminished. A peptide antagonist of TSP1-dependent TGF-beta activation prevented progression of cardiac fibrosis and improved cardiac function by reducing TGF-beta activity These data suggest that TSPI is a significant mediator of fibrotic complications of diabetes associated with stimulation of the renin-angiotensin system, and further studies to assess the blockade of TSPI-dependent TGF-13 activation as a potential anti-fibrotic therapeutic strategy are warranted.