Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments.
Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments.
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DOI：
10.2174/138945008785909347
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发表时间：
2008-10
影响因子：
3.2
通讯作者：
Volpert OV
中科院分区：
文献类型：
--
作者：
Mirochnik Y;Kwiatek A;Volpert OV
凝血酶敏感蛋白-1是第一个也是研究最多的天然血管生成蛋白抑制物。其特有的多结构域结构决定了凝血酶敏感蛋白-1具有不同的功能，包括但不限于对血管生成的调控。下面我们概述在内皮细胞和其他细胞类型上表达的结构决定因素和受体，它们是凝血酶敏感蛋白-1显著抑制新生血管能力的根源。我们特别强调凝血酶敏感蛋白-1在重建的血管内皮细胞上的直接凋亡作用，并总结了目前对其促凋亡信号和转录网络的知识。此外，我们对基于凝血酶敏感蛋白的抗血管生成策略进行了全面的综述，尤其是联合治疗。我们令人信服地说明了对血栓反应蛋白在血管内皮细胞中引发的促凋亡事件和中间体的精确知识如何促进最有效的治疗组合的设计，其中，血栓反应蛋白衍生化合物的疗效被合作药物(S)(“补充”策略)最大化，并提供了基于血栓反应蛋白的抗血管生成治疗的这种微调的例子。
Thrombospondin-1 is the first and most studied naturally occurring protein inhibitor of angiogenesis. Its characteristic multi-domain structure determines thrombospondin-1 divergent functions, which include but are not limited to the regulation of angiogenesis. Below we overview the structural determinants and receptors expressed on the endothelial and other cell types, that are at the root of thrombospondin-1 striking ability to block neovascularization. We specifically emphasize thrombospondin-1 direct apoptotic action on the remodeling vascular endothelium and summarize current knowledge of its pro-apoptotic signaling and transcriptional networks. Further, we provide comprehensive survey of the thrombospondin-based anti-angiogenic strategies with special focus on the combination treatments. We convincingly illustrate how precise knowledge of the pro-apoptotic events and intermediates elicited by thrombospondin in the vascular endothelial cells facilitates the design of the most effective treatment combinations, where the efficacy of thrombospondin-derived compounds is maximized by the partner drug(s) (“complementation” strategies) and provide examples of such fine-tuning of the thrombospondin-based anti-angiogenic treatments.