کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8475069 1550442 2013 31 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice
چکیده انگلیسی
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 (6 Hz, 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 63, October 2013, Pages 189-198
نویسندگان
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