Journal
BASIC RESEARCH IN CARDIOLOGY
Volume 108, Issue 3, Pages -Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-013-0349-x
Keywords
ANKRD1; Sarcomere; Engineered heart tissue; Hypertrophic cardiomyopathy
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Health, Labour and Welfare, Japan
- Association Francaise contre les Myopathie
- Tokyo Medical and Dental University
- Medical Research Institute Tokyo Medical and Dental University
- European Union [Health-F2-2009-241577]
- Grants-in-Aid for Scientific Research [25670172, 22390157, 23132507, 24790335, 25293181, 23659414] Funding Source: KAKEN
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Hypertrophic cardiomyopathy (HCM) is a myocardial disease associated with mutations in sarcomeric genes. Three mutations were found in ANKRD1, encoding ankyrin repeat domain 1 (ANKRD1), a transcriptional co-factor located in the sarcomere. In the present study, we investigated whether expression of HCM-associated ANKRD1 mutations affects contraction parameters after gene transfer in engineered heart tissues (EHTs). EHTs were generated from neonatal rat heart cells and were transduced with adeno-associated virus encoding GFP or myc-tagged wild-type (WT) or mutant (P52A, T123M, or I280V) ANKRD1. Contraction parameters were analyzed from day 8 to day 16 of culture, and evaluated in the absence or presence of the proteasome inhibitor epoxomicin for 24 h. Under standard conditions, only WT- and T123M-ANKRD1 were correctly incorporated in the sarcomere. T123M-ANKRD1-transduced EHTs exhibited higher force and velocities of contraction and relaxation than WT- P52A- and I280V-ANKRD1 were highly unstable, not incorporated into the sarcomere, and did not induce contractile alterations. After epoxomicin treatment, P52A and I280V were both stabilized and incorporated into the sarcomere. I280V-transduced EHTs showed prolonged relaxation. These data suggest different impacts of AN-KRD1 mutations on cardiomyocyte function: gain-offunction for T123M mutation under all conditions and dominant-negative effect for the I280V mutation which may come into play only when the proteasome is impaired.
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