Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
Circ Res. 2010 May 14;106(9):1524-32. doi: 10.1161/CIRCRESAHA.109.212639. Epub 2010 Apr 1.
Transgenic mice with cardiac specific overexpression of mutated alphaB-crystallin (CryAB(R120G)) 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 CryAB(R120G) 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 CryAB(R120G) pathology and decrease morbidity.
We crossed CryAB(R120G) mice to transgenic mice with cardiac specific overexpression of Bcl-2. Sustained Bcl-2 overexpression in CryAB(R120G) hearts prolonged CryAB(R120G) transgenic mice survival by 20%. This was associated with decreased mitochondrial abnormalities, restoration of cardiac function, prevention of cardiac hypertrophy, and attenuation of apoptosis. CryAB(R120G) 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.
Although Bcl-2 overexpression prolonged life in this DRM model, in the absence of apoptosis, another death pathway was activated.
在心脏特异性过表达突变型αB-晶体蛋白（CryAB（R120G））的转基因小鼠中，出现了伴有扩张型心肌病和心力衰竭的肌原纤维相关肌病（DRM）。我们之前的研究表明，CryAB（R120G）转基因心脏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疾病发展过程中的作用尚不清楚。
我们检验了这样一个假设，即阻止细胞凋亡将改善 CryAB（R120G）病理学并降低发病率。
我们将 CryAB（R120G）小鼠与心脏特异性过表达 Bcl-2 的转基因小鼠杂交。CryAB（R120G）心脏中持续的 Bcl-2 过表达使 CryAB（R120G）转基因小鼠的存活时间延长了 20%。这与线粒体异常的减少、心脏功能的恢复、心脏肥大的预防以及凋亡的减弱有关。在双转基因小鼠中，CryAB（R120G）错误折叠蛋白聚集体显著减少。然而，凋亡信号的抑制导致自噬和替代死亡途径的上调，其净结果是坏死增加。
尽管 Bcl-2 的过表达延长了这种 DRM 模型中的寿命，但在没有凋亡的情况下，另一种死亡途径被激活。
