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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice
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Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice

机译：Mybpc3靶向敲入小鼠的工程心脏组织中的收缩异常和改变的药物反应

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摘要

Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C. EHTs were generated from cardiac cells of neonatal KI, heterozygous (HET) or wild-type controls (WT) and developed without apparent morphological differences. KI had 70% and HET 20% lower total cMyBP-C levels than WT, accompanied by elevated fetal gene expression. Under standard culture conditions and spontaneous beating, KI EHTs showed more frequent burst beating than WT and occasional tetanic contractions (14/96). Under electrical stimulation (6Hz, 37°C) KI EHTs exhibited shorter contraction and relaxation times and a twofold higher sensitivity to external [Ca2+]. Accordingly, the sensitivity to verapamil was 4-fold lower and the response to isoprenaline or the Ca2+ sensitizer EMD 57033 2- to 4-fold smaller. The loss of EMD effect was verified in 6-week-old KI mice in vivo. HET EHTs were apparently normal under basal conditions, but showed similarly altered contractile responses to [Ca2+], verapamil, isoprenaline and EMD. In contrast, drug-induced changes in intracellular Ca2+ transients (Fura-2) were essentially normal. In conclusion, the present findings in auxotonically contracting EHTs support the idea that cMyBP-C's normal role is to suppress force generation at low intracellular Ca2+ and stabilize the power-stroke step of the cross bridge cycle. Pharmacological testing in EHT unmasked a disease phenotype in HET. The altered drug response may be clinically relevant.
机译：靶向肌球蛋白结合蛋白C（Mybpc3）的敲入小鼠（KI）概括了人类肥厚型心肌病的典型方面。我们评估了这些功能改变是否可以在工程心脏组织（EHT）中复制并产生有关cMyBP-C功能的新颖机制信息。 EHTs是从新生儿KI，杂合子（HET）或野生型对照（WT）的心脏细胞生成的，并且发育时没有明显的形态学差异。 KI的总cMyBP-C水平比WT低70％，HET低20％，并伴有胎儿基因表达升高。在标准培养条件下和自发搏动下，KI EHT的爆裂搏动比WT和偶发的强直性收缩更为频繁（14/96）。在电刺激（6Hz，37°C）下，KI EHTs表现出更短的收缩和弛豫时间，对外部[Ca2 +]的敏感性高两倍。因此，对维拉帕米的敏感性降低了4倍，对异丙肾上腺素或Ca2 +敏化剂EMD 57033的响应降低了2至4倍。在6周龄的KI小鼠体内证实了EMD作用的丧失。在基础条件下，HET EHTs显然是正常的，但对[Ca2 +]，维拉帕米，异丙肾上腺素和EMD的收缩反应表现出相似的变化。相反，药物诱导的细胞内Ca2 +瞬变（Fura-2）的变化基本上是正常的。总而言之，目前在等渗收缩EHT中的发现支持了cMyBP-C的正常作用是抑制低细胞内Ca2 +产生的力并稳定跨桥循环的动力冲程步骤这一观点。 EHT的药理学测试揭示了HET中的疾病表型。改变的药物反应可能与临床有关。

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