LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice.
LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice.
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DOI：
10.1016/j.ijcard.2009.08.047
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发表时间：
2011-03-03
影响因子：
3.5
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Zhang T;Yong SL;Drinko JK;Popović ZB;Shryock JC;Belardinelli L;Wang QK
Mutations in the cardiac sodium channel gene SCN5A cause long QT syndrome (LQTS). We previously generated a LQTS mouse model (TG-NS) that overexpresses LQTS mutation N1325S in SCN5A. The TG-NS mice manifested the clinical features of LQTS including spontaneous VT, syncope and sudden death. However, the long-term prognosis of LQTS on the structure of the heart has not been investigated in this or any other LQTS models and human patients. Impaired systolic function and reduced left ventricular fractional shortening were detected by echocardiography, morphological and histological examination in two lines of adult mutant transgenic mice. Histological and TUNEL analyses of heart sections revealed fibrosis lesions and increased apoptosis in an age-dependent manner. Cardiomyocyte apoptosis was associated with increased activation of caspases 3 and 9 in TG-NS hearts. Western blot analysis showed significantly increased expression of key Ca2+ handling proteins L-type Ca2+ channel, RYR2 and NCX in TG-NS hearts. Increased apoptosis and altered expression of Ca2+ handling proteins could be detected as young as 3 months of age when echocardiographic showed little or no alterations in TG-NS mice. Our findings revealed for the first time that LQTS mutation N1325S in SCN5A causes cardiac fibrosis and contractile dysfunction in mice, possibly through cellular mechanisms involving aberrant cardiomyocyte apoptosis. Therefore, we provide the experimental evidence supporting the notion that some LQTS patients have an increased risk of structural and functional cardiac damage in a prolonged disease course.
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