Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe cardiomyopathic phenotype
Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe cardiomyopathic phenotype
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DOI：
10.1016/s0002-9440(10)61168-6
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发表时间：
2002-06-01
影响因子：
6
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
--
作者：
Park, DS;Woodman, SE;Lisanti, MP
小窝蛋白基因家族由小窝蛋白1、2和3组成。小窝蛋白1和2在许多细胞类型中共表达，例如内皮细胞、成纤维细胞、平滑肌细胞和脂肪细胞，其中它们形成异源寡聚体复合物。相反，小窝蛋白-3的表达是肌肉特异性的。因此，小窝蛋白-1的表达是非肌肉细胞中小窝形成所必需的，而小窝蛋白-3的表达驱动横纹肌细胞类型（心脏和骨骼肌）中小窝形成。为了产生真正的小窝缺陷小鼠，我们将Cav-1缺失小鼠和Cav-3缺失小鼠杂交以产生Cav-1/Cav-3双敲除（Cav-1/3 dKO）小鼠。在这里，我们报告说，Cav-1/3 dKO小鼠是可行的和肥沃的，尽管事实上，他们缺乏形态学上可识别的小窝在内皮细胞，脂肪细胞，平滑肌细胞，骨骼肌纤维，心肌细胞。我们还表明，这些小鼠缺乏所有三个小窝蛋白基因产物，因为小窝蛋白-2在没有小窝蛋白-1的情况下是不稳定的。有趣的是，Cav-1/3 dKO小鼠发生严重的心肌病。在2月龄时，通过门控磁共振成像对Cav-1/3 dKO心脏的分析显示，与Cav-1-KO、Cav-3 KO和野生型小鼠相比，左心室壁厚度显著增加。通过经胸超声心动图对Cav-1/3 dKO心脏的进一步功能分析表明左心室肥大和扩张，缩短分数显著降低。正如所预测的，对Cav-1/3 dKO小鼠左心室RNA的北方分析显示心房利钠因子信息显著上调，心房利钠因子信息是心脏肥大的一种公认的生化标志物。最后，Cav-1/3 dKO心脏的组织学分析揭示了心肌细胞的肥大、解体和变性，以及慢性间质纤维化和炎症。因此，在小鼠中Cav-1和Cav-3基因的双重消融导致小窝形成的多效性缺陷和严重的心肌病。
The caveolin gene family consists of caveolins 1, 2, and 3. Caveolins 1 and 2 are co-expressed in many cell types, such as endothelial cells, fibroblasts, smooth muscle cells and adipocytes, where they form a heteroligomeric complex. In contrast, the expression of caveolin-3 is muscle-specific. Thus, the expression of caveolin-1 is required for caveolae formation in nonmuscle cells, while the expression of caveolin-3 drives caveolae formation in striated muscle cell types (cardiac and skeletal). To create a truly caveolae-deficient mouse, we interbred Cav-1 null mice and Cav-3 null mice to generate Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice. Here, we report that Cav-1/3 dKO mice are viable and fertile, despite the fact that they lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes. We also show that these mice are deficient in all three caveolin gene products, as caveolin-2 is unstable in the absence of caveolin-1. Interestingly, Cav-1/3 dKO mice develop a severe cardiomyopathy. At 2 months of age, analysis of Cav-1/3 dKO hearts via gated magnetic resonance imaging reveals a dramatic increase in left ventricular wall thickness, as compared with Cav-1-KO, Cav-3 KO, and wild-type mice. Further functional analysis of Cav-1/3 dKO hearts via transthoracic echocardiography demonstrates hypertrophy and dilation of the left ventricle, with a significant decrease in fractional shortening. As predicted, Northern analysis of RNA derived from the left ventricle of Cav-1/3 dKO mice shows a dramatic up-regulation of the atrial natriuretic factor message, a well-established biochemical marker of cardiac hypertrophy. Finally, histological analysis of Cav-1/3 dKO hearts reveals hypertrophy, disorganization, and degeneration of the cardiac myocytes, as well as chronic interstitial fibrosis and inflammation. Thus, dual ablation of both Cav-1 and Cav-3 genes in mice leads to a pleiotropic defect in caveolae formation and severe cardiomyopathy.