Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene
Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene
复制标题
DOI：
10.1161/01.res.0000231289.63468.08
复制
发表时间：
2006-07-07
影响因子：
20.1
通讯作者：
Kajstura, Jan
中科院分区：
文献类型：
--
作者：
Rota, Marcello;LeCapitaine, Nicole;Kajstura, Jan
糖尿病导致失代偿性肌病，但心脏病的病因知之甚少。氧化应激随着糖尿病而增强，并且氧毒性可能改变心脏祖细胞（CPC）功能，导致CPC生长和肌细胞形成缺陷，这可能有利于心肌过早老化和心力衰竭。我们报告，在胰岛素依赖型糖尿病模型中，活性氧（ROS）的产生导致端粒缩短，衰老相关蛋白p53和p16（INK 4a）的表达，以及CPC的凋亡，损害心脏的生长储备。然而，p66（she）基因的消融可以防止CPC隔室的这些负性适应，干扰心脏衰老表型的获得和糖尿病心力衰竭的发展。ROS引发3种细胞反应：低水平激活细胞生长，中等量触发细胞凋亡，高量引发细胞坏死。CPC复制在糖尿病p66（she-/-）中占主导地位，而CPC凋亡和肌细胞凋亡和坏死在糖尿病野生型中占主导地位。CPCs的扩张和发育中的心肌细胞在糖尿病p66（she-/-）中保留了心脏功能，这表明完整的CPCs可以有效地抵消不受控制的糖尿病对心脏的影响。认识到p66（she）决定着CPC的命运，这就提出了糖尿病心肌病是一种干细胞疾病的可能性，在这种疾病中，CPC的异常决定了心脏的生死。总之，这些数据表明糖尿病和ROS之间存在遗传联系，另一方面，CPC的生存和生长。
Diabetes leads to a decompensated myopathy, but the etiology of the cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter cardiac progenitor cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16(INK4a), and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66(she) gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 cellular reactions: low levels activate cell growth, intermediate quantities trigger cell apoptosis, and high amounts initiate cell necrosis. CPC replication predominates in diabetic p66(she-/-), whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66(she-/-), suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66(she) conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a stem cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.