A novel scheme of dystrophin disruption for the progression of advanced heart failure
A novel scheme of dystrophin disruption for the progression of advanced heart failure
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DOI：
10.1016/j.bbapap.2005.01.001
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发表时间：
2005-08-01
影响因子：
3.2
通讯作者：
Toyo-oka, T
中科院分区：
文献类型：
--
作者：
Kawada, T;Masui, F;Toyo-oka, T
晚期心力衰竭进展的确切机制尚不清楚。我们在两种心力衰竭模型中评估了一种新的方案：（1）缺乏δ-肌聚糖（SG）基因的TO-2品系仓鼠的先天性扩张型心肌病（I）CM）和（11）给予高剂量异丙肾上腺素，作为正常大鼠的急性心力衰竭。在TO-2仓鼠中，我们跟踪了心力衰竭进展到终末期的组织学、生理学和代谢的时间过程。肌营养不良蛋白定位检测年龄依赖性的肌浆和原位肌膜脆性评估伊文思蓝进入增加在相同的心肌细胞。蛋白质印迹法显示肌营养不良蛋白在杆状结构域的有限切割，强烈表明内源性蛋白酶的贡献。我们发现钙蛋白酶-1和-2的量显著上调，而它们的对应物钙蛋白酶抑制蛋白没有变化。在体内用正常的delta-SG基因补充TO-2心脏后，这些病理改变和动物的存活率得到改善。此外，抗肌萎缩蛋白，但不是三角洲SG被破坏的高剂量的异丙肾上腺素，从肌膜易位到肌浆和碎片。心力衰竭的这些结果，无论是遗传性还是获得性起源，都表明由肌膜通透性增加、钙蛋白酶优先激活钙蛋白酶抑制蛋白以及肌营养不良蛋白的移位和切割形成的恶性循环通常会导致晚期心力衰竭。(c)2005 Elsevier B.V保留所有权利。
The precise mechanism of the progression of advanced heart failure is unknown. We assessed a new scheme in two heart failure models: (1) congenital dilated cardiomyopathy (I)CM) in TO-2 strain hamsters lacking delta-sarcoglycan (SG) gene and (11) administration of a high-dose of isoproterenol, as an acute heart failure in normal rats. In TO-2 hamsters, we followed the time course of the histological, physiological and metabolic the progressions of heart failure to the end stage. Dystrophin localization detected by immunostaining age-dependently to the myoplasm and the in situ sarcolemma fragility evaluated by Evans blue entry was increased in the same cardiomyocytes. Western blotting revealed a limited cleavage of the dystrophin protein at the rod domain, strongly suggesting a contribution of endogenous protease(s). We found a remarkable up-regulation of the amount of calpain- 1 and -2, and no change of their counterpart, calpastatin. After supplementing TO-2 hearts with the normal delta-SG gene in vivo, these pathological alterations and the animals' survival improved. Furthermore, dystrophin but not delta-SG was disrupted by a high dose of isoproterenol, translocated from the sarcolemma to the myoplasm and fragmented. These results of heart failure, irrespective of the hereditary or acquired origin, indicate a vicious cycle formed by the increased sarcolemma permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin would commonly lead to advanced heart failure. (c) 2005 Elsevier B.V All rights reserved.