Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction.
Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction.
复制标题
α-原肌球蛋白突变的家族性肥厚型心肌病小鼠模型表现出心脏功能障碍。
DOI：
10.1161/01.res.85.1.47
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发表时间：
1999
影响因子：
20.1
通讯作者：
Wieczorek,DF
中科院分区：
文献类型：
--
作者：
Muthuchamy,M;Pieples,K;Rethinasamy,P;Hoit,B;Grupp,IL;Boivin,GP;Wolska,B;Evans,C;Solaro,RJ;Wieczorek,DF
为了研究与家族性肥厚型心肌病（FHC）相关的原肌球蛋白（TM）突变的功能后果，我们在成年心脏中产生了表达突变α-TM的转基因小鼠。错义突变，其导致在氨基酸位置175处天冬酰胺被天冬氨酸取代，发生在TM的肌钙蛋白T结合区。S1核酸酶图谱和Western印迹分析表明，不同品系中α-TM 175转基因表达的增加导致内源性α-TM mRNA和蛋白表达水平的同时降低。体内生理分析显示FHC小鼠心脏的收缩性和舒张性均严重受损，左心室缩短分数发生显著变化。含有α-TM 175的肌丝通过增强稳态力的Ca 2+敏感性表现出对细丝的激活增加。组织学分析显示轻度心室肌细胞解体和肥大的斑片状区域，左心房偶见血栓形成。因此，FHC α-TM转基因小鼠可作为检查异常TM亚型引起的病理和生理变化的模型系统。
—To investigate the functional consequences of a tropomyosin (TM) mutation associated with familial hypertrophic cardiomyopathy (FHC), we generated transgenic mice that express mutant α-TM in the adult heart. The missense mutation, which results in the substitution of asparagine for aspartic acid at amino acid position 175, occurs in a troponin T binding region of TM. S1 nuclease mapping and Western blot analyses demonstrate that increased expression of the α-TM 175 transgene in different lines causes a concomitant decrease in levels of endogenous α-TM mRNA and protein expression. In vivo physiological analyses show a severe impairment of both contractility and relaxation in hearts of the FHC mice, with a significant change in left ventricular fractional shortening. Myofilaments that contain α-TM 175 demonstrate an increased activation of the thin filament through enhanced Ca2+sensitivity of steady-state force. Histological analyses show patchy areas of mild ventricular myocyte disorganization and hypertrophy, with occasional thrombi formation in the left atria. Thus, the FHC α-TM transgenic mouse can serve as a model system for the examination of pathological and physiological alterations imparted through aberrant TM isoforms.