LMNA E82K mutation activates FAS and mitochondrial pathways of apoptosis in heart tissue specific transgenic mice.
LMNA E82K mutation activates FAS and mitochondrial pathways of apoptosis in heart tissue specific transgenic mice.
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DOI：
10.1371/journal.pone.0015167
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发表时间：
2010-12-06
期刊：
影响因子：
3.7
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Lu D;Lian H;Zhang X;Shao H;Huang L;Qin C;Zhang L
核纤层蛋白A/C（LMNA）是核中间丝蛋白，是核纤层的基本组成部分。LMNA中的突变与广泛的核纤层蛋白病、影响组织再生和体内平衡的先天性疾病相关。产生了心脏组织特异性的人LMNA E82 K（一种引起扩张型心肌病的突变）转基因小鼠。Lmna E82 K转基因小鼠系表现出薄壁，扩张的左心室和右心室，通过超声心动图评估的收缩功能进行性下降。Lmna E82 K转基因小鼠心脏传导系统功能障碍，心肌细胞排列紊乱，胶原沉积，B型利钠肽（BNP）、Ⅲ型前胶原α1（Col 3 α1）和骨骼肌肌动蛋白α1（Actα1）水平升高。LMNA E82 K突变导致LMNA在细胞核中的错误定位和线粒体肿胀，伴随着critae的丧失，以及核膜完整性的丧失。最有趣的是，我们发现Lmna E82 K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LMNA E82 K存在下，FAS和线粒体凋亡途径均被激活，这与FAS表达的增加、细胞色素c从线粒体释放到细胞质以及半胱天冬酶-8、-9和-3的激活一致。结果提示，LMNA E82 K或核纤层蛋白A/C杆区突变引起的心肌细胞凋亡可能是导致心肌细胞持续丢失和心肌功能障碍的重要机制。这可能是一种潜在的治疗手段，以抑制和/或防止携带LMNA突变的患者的心脏细胞不适当的死亡。
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.
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影响因子：
3.5
作者：
Mounkes, LC;Kozlov, SV;Stewart, CL
通讯作者：
Stewart, CL
DOI：
10.1073/pnas.96.14.8144
发表时间：
1999-07-06
影响因子：
11.1
作者：
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DOI：
10.1016/s0022-2828(08)80028-4
发表时间：
1995-01-01
影响因子：
5
作者：
BELTRAMI, CA;FINATO, N;ANVERSA, P
通讯作者：
ANVERSA, P
影响因子：
10.8
作者：
Barac, YD;Zeevi-Levin, N;Binah, O
通讯作者：
Binah, O