Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue
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Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue. / Crocini, Claudia ; Arimura, Takuro; Reischmann, Silke; Eder, Alexandra; Braren, Ingke ; Hansen, Arne; Eschenhagen, Thomas; Kimura, Akinori; Carrier, Lucie.
In: BASIC RES CARDIOL, Vol. 108, No. 3, 01.01.2013, p. 349.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue
AU - Crocini, Claudia
AU - Arimura, Takuro
AU - Reischmann, Silke
AU - Eder, Alexandra
AU - Braren, Ingke
AU - Hansen, Arne
AU - Eschenhagen, Thomas
AU - Kimura, Akinori
AU - Carrier, Lucie
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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 ANKRD1 mutations on cardiomyocyte function: gain-of-function 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.
AB - 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 ANKRD1 mutations on cardiomyocyte function: gain-of-function 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.
KW - Animals
KW - Animals, Newborn
KW - Cardiomyopathy, Hypertrophic
KW - Cells, Cultured
KW - Dependovirus
KW - Fluorescent Antibody Technique
KW - Gene Expression Regulation
KW - Genetic Vectors
KW - Genotype
KW - Green Fluorescent Proteins
KW - Humans
KW - Muscle Proteins
KW - Mutation
KW - Myocardial Contraction
KW - Myocytes, Cardiac
KW - Nuclear Proteins
KW - Oligopeptides
KW - Phenotype
KW - Proteasome Endopeptidase Complex
KW - Proteasome Inhibitors
KW - Rats
KW - Repressor Proteins
KW - Time Factors
KW - Tissue Engineering
KW - Transduction, Genetic
KW - Transfection
U2 - 10.1007/s00395-013-0349-x
DO - 10.1007/s00395-013-0349-x
M3 - SCORING: Journal article
C2 - 23572067
VL - 108
SP - 349
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 3
ER -