Desensitization of Myofilaments to Ca2+ as a Therapeutic Target for Hypertrophic Cardiomyopathy With Mutations in Thin Filament Proteins
Desensitization of Myofilaments to Ca2+ as a Therapeutic Target for Hypertrophic Cardiomyopathy With Mutations in Thin Filament Proteins
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DOI：
10.1161/circgenetics.113.000324
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发表时间：
2014-04-01
影响因子：
--
通讯作者：
Wolska, Beata M.
中科院分区：
文献类型：
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作者：
Alves, Marco L.;Dias, Fernando A. L.;Wolska, Beata M.
背景-肥厚性心肌病(HCM)是一种常见的遗传性疾病，主要由肌节蛋白突变引起，其特征是适应性不良的心肌肥厚、舒张性心力衰竭、肌丝钙敏感性增加和猝死的高易感性。我们测试了以下假设：纠正增加的肌丝敏感性可以延缓或防止HCM表型的发展。方法和结果-我们使用了α-原肌球蛋白(Tm180)E180G突变的HCM小鼠模型，显示出肌丝对钙的敏感性增加，严重的肥厚和舒张期功能障碍。为了验证我们的假设，我们通过建立一个双转基因小鼠系来降低Tm180小鼠的肌丝钙敏感性。我们将Tm180小鼠与表达假磷酸化心肌肌钙蛋白I(S23D和S24D；TnI-PP)的小鼠杂交。与野生型小鼠相比，TnI-PP小鼠表现出对肌丝钙的敏感性降低。同时表达Tm180和TnI-PP的小鼠未出现病理性肥大。与表达野生型心肌肌钙蛋白I的Tm180小鼠相比，双转基因小鼠的左心功能得到改善。与Tm180小鼠相比，双转基因小鼠的心脏中磷蛋白和肌浆网钙ATPase的表达没有变化，磷蛋白和肌钙蛋白T的磷酸化水平增加，而TnI的磷酸化水平降低。此外，Tm180心脏中TnI-PP的表达抑制了Tm180心脏细胞外信号调节激酶和含锌指转录因子GATA活性的改变。结论-我们的数据有力地表明，降低肌丝对钙的敏感性并伴随着异常松弛的纠正可以延缓或防止肥厚性心肌病的发展，应作为肥厚性心肌病的治疗靶点。
Background-Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca2+ sensitivity, and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype.Methods and Results-We used an HCM mouse model with an E180G mutation in alpha-tropomyosin (Tm180) that demonstrates increased myofilament Ca2+ sensitivity, severe hypertrophy, and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca2+ sensitivity in Tm180 mice by generating a double transgenic mouse line. We crossed Tm180 mice with mice expressing a pseudophosphorylated cardiac troponin I (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca2+ sensitivity compared with wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in double transgenic compared with their Tm180 littermates, which express wild-type cardiac troponin I. Hearts of double transgenic mice demonstrated no changes in expression of phospholamban and sarcoplasmic reticulum Ca2+ ATPase, increased levels of phospholamban and troponin T phosphorylation, and reduced phosphorylation of TnI compared with Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of extracellular signal-regulated kinase and zinc finger-containing transcription factor GATA in Tm180 hearts.Conclusions-Our data strongly indicate that reduction of myofilament sensitivity to Ca2+ and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.