Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model.
Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model.
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DOI：
10.3390/ijms23168840
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发表时间：
2022-08-09
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
心肌肌球蛋白结合蛋白C（cMyBP-C）的变异体是遗传性肥厚型心肌病（HCM）的主要原因，这表明cMyBP-C在心脏收缩机制中起着关键作用。为了研究c-MYBPC 3 HCM相关的心脏损害，我们产生了斑马鱼mypbc 3敲除模型。这些基因敲除斑马鱼显示出显着的心脏形态学改变相关的心室和心房的直径在收缩和舒张状态在幼虫阶段的显着减少。免疫荧光染色显示突变体的总心脏和心室心肌细胞显著增生。虽然心肌收缩力与野生型对照组相似，但mypbc 3突变体的射血分数显著增加。在幼虫发育的后期阶段，突变体表现出心肌重塑的早期心脏表型，同时心肌细胞增生和射血分数增加作为HCM启动的关键过程，以抵消增加的心室心肌壁应力。对成年斑马鱼的检查显示，mypbc 3杂合子和纯合子组的心室心壁增厚，心率、游泳速度和耐力降低。此外，心脏转录组分析显示肌动蛋白丝为基础的过程的显着下调，表明受损的肌动蛋白细胞骨架组织的主要失调因素与早期心室心肌肥大在斑马鱼mypbc 3 HCM模型。
Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart’s contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant’s total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model.
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影响因子：
5.6
作者：
Cornet C;Calzolari S;Miñana-Prieto R;Dyballa S;van Doornmalen E;Rutjes H;Savy T;D'Amico D;Terriente J
通讯作者：
Terriente J
影响因子：
2.9
作者：
Belknap, Betty;Harris, Samantha P.;White, Howard D.
通讯作者：
White, Howard D.
影响因子：
4
作者：
Farrell ET;Grimes AC;de Lange WJ;Armstrong AE;Ralphe JC
通讯作者：
Ralphe JC
影响因子：
20.3
作者：
Da'as, Sahar I.;Coombs, Andrew J.;Berman, Jason N.
通讯作者：
Berman, Jason N.
脊椎动物心脏传导系统的遗传和生理解剖。
影响因子：
9.8
作者：
Chi NC;Shaw RM;Jungblut B;Huisken J;Ferrer T;Arnaout R;Scott I;Beis D;Xiao T;Baier H;Jan LY;Tristani-Firouzi M;Stainier DY
通讯作者：
Stainier DY