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Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin.

ABSTRACT: The electrophysiological consequences of cardiomyocyte and myofibroblast interactions remain unclear, and the contribution of mechanical coupling between these two cell types is still poorly understood. In this study, we examined the time course and mechanisms by which addition of myofibroblasts activated by transforming growth factor-beta (TGF-?) influence the conduction velocity (CV) of neonatal rat ventricular cell monolayers. We observed that myofibroblasts affected CV within 30 min of contact and that these effects were temporally correlated with membrane deformation of cardiomyocytes by the myofibroblasts. Expression of dominant negative RhoA in the myofibroblasts impaired both myofibroblast contraction and myofibroblast-induced slowing of cardiac conduction, whereas overexpression of constitutive RhoA had little effect. To determine the importance of mechanical coupling between these cell types, we examined the expression of the two primary cadherins in the heart (N- and OB-cadherin) at cell-cell contacts formed between myofibroblasts and cardiomyocytes. Although OB-cadherin was frequently found at myofibroblast-myofibroblast contacts, very little expression was observed at myofibroblast-cardiomyocyte contacts. The myofibroblast-induced slowing of cardiac conduction was not prevented by silencing of OB-cadherin in the myofibroblasts, and could be reversed by inhibitors of mechanosensitive channels (gadolinium or streptomycin) and cellular contraction (blebbistatin). In contrast, N-cadherin expression was commonly observed at myofibroblast-cardiomyocyte contacts, and silencing of N-cadherin in myofibroblasts prevented the myofibroblast-dependent slowing of cardiac conduction. We propose that myofibroblasts can impair the electrophysiological function of cardiac tissue through the application of contractile force to the cardiomyocyte membrane via N-cadherin junctions.

SUBMITTER: Thompson SA

PROVIDER: S-EPMC3993970 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin.

Thompson Susan A SA Blazeski Adriana A Copeland Craig R CR Cohen Daniel M DM Chen Christopher S CS Reich Daniel M DM Tung Leslie L

Journal of molecular and cellular cardiology 20140109

The electrophysiological consequences of cardiomyocyte and myofibroblast interactions remain unclear, and the contribution of mechanical coupling between these two cell types is still poorly understood. In this study, we examined the time course and mechanisms by which addition of myofibroblasts activated by transforming growth factor-beta (TGF-β) influence the conduction velocity (CV) of neonatal rat ventricular cell monolayers. We observed that myofibroblasts affected CV within 30 min of conta ...[more]

PMID: 24412534

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Project description: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.The role of mechanoelectric feedback was examined in transforming growth factor-?-treated monolayers of cocultured myofibroblasts and neonatal rat ventricular cells by inhibiting myofibroblast contraction and blocking mechanosensitive channels. Untreated (control) and transforming growth factor-?-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-?, a decrease with blebbistatin, and no change with mechanosensitive channel blockers.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.

Project description:BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5±0.4 and 12.6±0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3±1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3±1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1±1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9±1.0 cm/s, p = NS vs. control).ConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.

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Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin.

Publications

Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin.

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