コンテンツへスキップ
Merck
  • Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.

iScience (2024-08-05)
Xinghang Jiang, Olivia T Ly, Hanna Chen, Ziwei Zhang, Beatriz A Ibarra, Mahmud A Pavel, Grace E Brown, Arvind Sridhar, David Tofovic, Abigail Swick, Richard Marszalek, Carlos G Vanoye, Fritz Navales, Alfred L George, Salman R Khetani, Jalees Rehman, Yu Gao, Dawood Darbar, Ankur Saxena
要旨

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna Δ9/Δ9 zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.

材料
製品番号
ブランド
製品内容

Roche
cOmplete、ミニ、EDTA フリー、プロテアーゼ阻害剤カクテル, Protease Inhibitor Cocktail Tablets provided in a glass vial, Tablets provided in a glass vial
Sigma-Aldrich
HMR-1556, ≥98% (HPLC)