Manipulation of death pathways in desmin-related cardiomyopathy.
Manipulation of death pathways in desmin-related cardiomyopathy.
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DOI：
10.1161/circresaha.109.212639
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发表时间：
2010-05-14
影响因子：
20.1
通讯作者：
Robbins J
中科院分区：
文献类型：
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作者：
Maloyan A;Sayegh J;Osinska H;Chua BH;Robbins J
心脏特异性过表达突变型α B-晶状体蛋白（CryABR120G）的转基因小鼠显示结蛋白相关肌病（DRM）伴扩张型心肌病和心力衰竭。我们以前的研究表明，在CryABR120G转基因心脏中存在进行性线粒体异常和凋亡细胞死亡的激活。然而，线粒体功能障碍和细胞凋亡在整个疾病过程中的作用尚不清楚。我们检验了预防细胞凋亡将改善CryABR120G病理学并降低发病率的假设。我们将CryABR120G小鼠与心脏特异性过表达Bcl-2的转基因小鼠杂交。在CryABR120G心脏中持续的Bcl-2过表达使CryABR120G转基因小鼠的存活时间延长了20%。这与线粒体异常减少、心脏功能恢复、预防心脏肥大和细胞凋亡减弱有关。双转基因中CryABR120 G错误折叠的蛋白质聚集显着减少。然而，凋亡信号的抑制导致自噬和替代死亡途径的上调，最终结果是坏死增加。虽然Bcl-2过表达延长了该DRM模型中的生命，但在没有细胞凋亡的情况下，另一种死亡途径被激活。
Transgenic mice with cardiac specific overexpression of mutated αB-crystallin (CryABR120G) display Desmin Related Myopathy (DRM) with dilated cardiomyopathy and heart failure. Our previous studies showed the presence of progressive mitochondrial abnormalities and activation of apoptotic cell death in CryABR120G transgenic hearts. However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear. We tested the hypothesis that prevention of apoptosis would ameliorate CryABR120G pathology and decrease morbidity. We crossed CryABR120G mice to transgenic mice with cardiac specific overexpression of Bcl-2. Sustained Bcl-2 overexpression in CryABR120G hearts prolonged CryABR120G transgenic mice survival by 20%. This was associated with decreased mitochondrial abnormalities, restoration of cardiac function, prevention of cardiac hypertrophy, and attenuation of apoptosis. CryABR120G misfolded protein aggregation was significantly reduced in the double transgenic. However, inhibition of apoptotic signaling resulted in the upregulation of autophagy and alternative death pathways, the net result being increased necrosis. While Bcl-2 overexpression prolonged life in this DRM model, in the absence of apoptosis, another death pathway was activated.