De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.
De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.
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瞬时受体电位M4(Trpm4)是Trp家族离子通道中的一个不寻常的成员，其作用目前还知之甚少。利用脊髓损伤的啮齿动物模型，我们研究了Trpm4在继发性出血与毛细血管碎裂相关的进行性扩大中的作用，这是中枢神经系统继发性损伤最具破坏性的机制。Trpm4mRNA和蛋白在毛细血管碎裂和点状出血形成前大量上调。Trpm4的体外表达使COS-7细胞对ATP耗竭后的肿胀和死亡高度敏感。脊髓损伤后，Trpm4反义治疗的大鼠或Trpm4−/−小鼠的体内基因抑制保留了毛细血管结构的完整性，消除了继发性出血，使损伤体积减少了三到五倍，并显著改善了神经功能。据我们所知，这是第一例必须经历从头表达的色氨酸通道，以表现中枢神经系统的病理。
The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4−/− mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.
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