Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice.
Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice.
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DOI：
10.1016/j.yjmcc.2012.03.009
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发表时间：
2012-06
影响因子：
5
通讯作者：
Carrier L
中科院分区：
文献类型：
--
作者：
Fraysse B;Weinberger F;Bardswell SC;Cuello F;Vignier N;Geertz B;Starbatty J;Krämer E;Coirault C;Eschenhagen T;Kentish JC;Avkiran M;Carrier L
肥厚型心肌病（HCM）通常由编码心肌肌球蛋白结合蛋白C（cMyBP-C）的MYBPC 3突变引起。从基因突变到HCM表型的机制仍然不完全清楚，部分原因是目前的HCM小鼠模型不能忠实地反映人类的情况，早期肥大混淆了对功能改变的解释。本研究的目的是评估心肌肌丝钙敏感化和舒张功能障碍是否与肥厚型心肌病左心室肥厚（LVH）的发生相关或先于LVH的发生。我们评估了皮肤和完整心肌细胞的功能，以及最近开发的Mybpc 3靶向基因敲入小鼠模型中的完整心脏，该模型携带经常与HCM相关的点突变。与野生型相比，10周龄纯合子基因敲入小鼠表现出i）皮肤心室小梁中肌丝Ca 2+敏感性较高，ii）舒张期肌节长度较低，完整肌细胞中Ca 2+瞬时衰减较快，iii）LVH，缩短分数降低，超声心动图和多普勒分析显示E/A和E′/A′较低，E/E′比值较高，提示收缩和舒张功能障碍。与此相反，杂合基因敲入小鼠，模仿人类HCM的情况，没有表现出左心室肥厚或收缩功能障碍，但表现出较高的肌丝Ca 2+敏感性，更快的Ca 2+瞬时衰减，舒张功能障碍。这些数据表明，肌丝Ca 2+敏化和舒张功能障碍是独立于LVH的Mybpc 3突变的早期表型结果。加速的Ca 2+瞬变指向针对放松正常化的补偿机制。我们建议HCM是舒张性心力衰竭的模型，并且这种小鼠模型在研究机制和治疗方式方面可能是有价值的。在杂合Mybpc 3靶向基因敲入小鼠中不存在左心室肥大。在杂合Mybpc 3靶向基因敲入小鼠中的肌丝Ca 2+敏化。心舒张功能不全与左心室肥厚无关。肥厚型心肌病作为舒张性心力衰竭的模型。
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from gene mutations to the HCM phenotype remain incompletely understood, partially because current mouse models of HCM do not faithfully reflect the human situation and early hypertrophy confounds the interpretation of functional alterations. The goal of this study was to evaluate whether myofilament Ca2+ sensitization and diastolic dysfunction are associated or precede the development of left ventricular hypertrophy (LVH) in HCM. We evaluated the function of skinned and intact cardiac myocytes, as well as the intact heart in a recently developed Mybpc3-targeted knock-in mouse model carrying a point mutation frequently associated with HCM. Compared to wild-type, 10-week old homozygous knock-in mice exhibited i) higher myofilament Ca2+ sensitivity in skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster Ca2+ transient decay in intact myocytes, and iii) LVH, reduced fractional shortening, lower E/A and E′/A′, and higher E/E′ ratios by echocardiography and Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit LVH or systolic dysfunction, but exhibited higher myofilament Ca2+ sensitivity, faster Ca2+ transient decay, and diastolic dysfunction. These data demonstrate that myofilament Ca2+ sensitization and diastolic dysfunction are early phenotypic consequences of Mybpc3 mutations independent of LVH. The accelerated Ca2+ transients point to compensatory mechanisms directed towards normalization of relaxation. We propose that HCM is a model for diastolic heart failure and this mouse model could be valuable in studying mechanisms and treatment modalities. ► Absence of left ventricular hypertrophy in heterozygous Mybpc3-targeted knock-in mice. ► Myofilament Ca2+ sensitization in heterozygous Mybpc3-targeted knock-in mice. ► Diastolic dysfunction independent of left ventricular hypertrophy. ► Hypertrophic cardiomyopathy as a model of diastolic heart failure.
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影响因子：
20.1
作者：
Harris SP;Lyons RG;Bezold KL
通讯作者：
Bezold KL
影响因子：
20.1
作者：
Lovelock JD;Monasky MM;Jeong EM;Lardin HA;Liu H;Patel BG;Taglieri DM;Gu L;Kumar P;Pokhrel N;Zeng D;Belardinelli L;Sorescu D;Solaro RJ;Dudley SC Jr
通讯作者：
Dudley SC Jr
影响因子：
37.8
作者：
MARON, BJ;GARDIN, JM;BILD, DE
通讯作者：
BILD, DE
影响因子：
39.3
作者：
Charron, P;Dubourg, O;Komajda, M
通讯作者：
Komajda, M
影响因子：
82.9
作者：
Georgakopoulos, D;Christe, ME;Kass, DA
通讯作者：
Kass, DA