Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, China.
PLoS One. 2010 Dec 6;5(12):e15167. doi: 10.1371/journal.pone.0015167.
The lamin A/C (LMNA), nuclear intermediate filament proteins, is a basic component of the nuclear lamina. Mutations in LMNA are associated with a broad range of laminopathies, congenital diseases affecting tissue regeneration and homeostasis. Heart tissue specific transgenic mice of human LMNA E82K, a mutation causing dilated cardiomyopathy, were generated. Lmna(E82K) transgenic mouse lines exhibited thin-walled, dilated left and right ventricles, a progressive decrease of contractile function assessed by echocardiography. Abnormalities of the conduction system, myocytes disarray, collagen accumulation and increased levels of B-type natriuretic peptide (BNP), procollagen type III α1 (Col3α1) and skeletal muscle actin α1 (Actα1) were detected in the hearts of Lmna(E82K) transgenic mice. The LMNA E82K mutation caused mislocation of LMNA in the nucleus and swollen mitochondria with loss of critae, together with the loss of nuclear envelope integrity. Most interestingly, we found that the level of apoptosis was 8.5-fold higher in the Lmna(E82K) transgenic mice than that of non-transgenic (NTG) mice. In the presence of the LMNA E82K, both of FAS and mitochondrial pathways of apoptosis were activated consistent with the increase of FAS expression, the release of cytochrome c from mitochondria to cytosol and activation of caspase-8, -9 and -3. Our results suggested that the apoptosis, at least for the LMNA E82K or the mutations in the rod region of Lamin A/C, might be an important mechanism causing continuous loss of myocytes and lead to myocardial dysfunction. It could be a potential therapeutic means to suppress and/or prevent inappropriate cardiac cell death in patients carrying LMNA mutation.
核纤层蛋白 A/C（LMNA）是核纤层的基本组成部分，是核中间丝蛋白。LMNA 突变与广泛的核纤层病有关，这些疾病影响组织再生和内稳态。生成了携带导致扩张型心肌病的人类 LMNA E82K 突变的心脏组织特异性转基因小鼠。Lmna（E82K）转基因小鼠线表现出薄壁、扩张的左、右心室，通过超声心动图评估收缩功能逐渐下降。在 Lmna（E82K）转基因小鼠的心脏中检测到传导系统异常、肌细胞排列紊乱、胶原蛋白积累和 B 型利钠肽（BNP）、III 型前胶原 α1（Col3α1）和骨骼肌肌动蛋白 α1（Actα1）水平升高。LMNA E82K 突变导致 LMNA 在核内定位错误和线粒体肿胀，嵴丢失，核膜完整性丧失。最有趣的是，我们发现 Lmna（E82K）转基因小鼠的细胞凋亡水平比非转基因（NTG）小鼠高 8.5 倍。在存在 LMNA E82K 的情况下，FAS 和线粒体凋亡途径均被激活，与 FAS 表达增加、细胞色素 c 从线粒体释放到细胞质以及 caspase-8、-9 和 -3 的激活一致。我们的结果表明，凋亡至少对于 LMNA E82K 或 lamin A/C 的杆状区突变，可能是导致心肌细胞持续丢失并导致心肌功能障碍的重要机制。抑制和/或预防携带 LMNA 突变的患者中不适当的心脏细胞死亡可能是一种潜在的治疗手段。
