Mechanical Coupling Between Myofibroblasts and Cardiomyocytes Slows Electric Conduction in Fibrotic Cell Monolayers

Article

关键词: CARDIAC FIBROBLASTS;    MECHANOELECTRIC FEEDBACK;    TGF-BETA;    FUNCTIONAL-CHARACTERIZATION;    MYOCARDIAL-INFARCTION;    IMPULSE CONDUCTION;    ION CHANNELS;    MYOCYTES;    CONTRACTION;    REENTRY;   

DOI  :  10.1161/CIRCULATIONAHA.110.015057

来源: SCIE

【 摘 要 】

Background-After cardiac injury, activated cardiac myofibroblasts can influence tissue electrophysiology. Because mechanical coupling through adherens junctions provides a route for intercellular communication, we tested the hypothesis that myofibroblasts exert tonic contractile forces on the cardiomyocytes and affect electric propagation via a process of mechanoelectric feedback. Methods and Results-The role of mechanoelectric feedback was examined in transforming growth factor-beta-treated monolayers of cocultured myofibroblasts and neonatal rat ventricular cells by inhibiting myofibroblast contraction and blocking mechanosensitive channels. Untreated (control) and transforming growth factor-beta-treated (fibrotic) anisotropic monolayers were optically mapped for electrophysiological comparison. Longitudinal conduction velocity, transverse conduction velocity, and normalized action potential upstroke velocity (dV/dt(max)) significantly decreased in fibrotic monolayers (14.4+/-0.7 cm/s [mean+/-SEM], 4.1+/-0.3 cm/s [n=53], and 3.1+/-0.2% per ms [n=14], respectively) compared with control monolayers (27.2+/-0.8 cm/s, 8.5+/-0.4 cm/s [n=40], and 4.9+/-0.1% per ms [n=12], respectively). Application of the excitation-contraction uncoupler blebbistatin or the mechanosensitive channel blocker gadolinium or streptomycin dramatically increased longitudinal conduction velocity, transverse conduction velocity, and dV/dt(max) in fibrotic monolayers (35.9+/-1.5 cm/s, 10.3+/-0.6 cm/s [n=17], and 4.5+/-0.1% per ms [n=14], respectively). Similar results were observed with connexin43-silenced cardiac myofibroblasts. Spiral-wave induction in fibrotic monolayers also decreased after the aforementioned treatments. Finally, traction force measurements of individual myofibroblasts showed a significant increase with transforming growth factor-beta, a decrease with blebbistatin, and no change with mechanosensitive channel blockers. Conclusions-These observations suggest that myofibroblast-myocyte mechanical interactions develop during cardiac injury, and that cardiac conduction may be impaired as a result of increased mechanosensitive channel activation owing to tension applied to the myocyte by the myofibroblast. (Circulation. 2011;123:2083-2093.)

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