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-β) influence the conduction velocity (CV) of neonatal rat ventricular cell monolayers. We observed that myofibroblasts affected CV within 30 minutes 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.

Transplantation of adipose tissue-derived stem cells improves cardiac contractile function and electrical stability in a rat myocardial infarction model

“…Although the precise mechanism underlying the reduced and less dispersed conduction velocity in the recipients of ADSCs remains unclear, the hearts of ADSC recipients demonstrated a smaller scar size, and increased myofibroblasts were present in both the scar and border areas. Myofibroblasts, which are converted from fibroblasts after cardiac injury, interact electrically with cardiomyocytes [36] and slow the conduction velocity [33]. Inconsistent with the current findings, Hwang et al showed that injection of conditioned medium from MSCs cultured under hypoxic conditions increased the conduction velocity in the border zone, resulting in a lower incidence of VT [13].…”

“…Recently, myofibroblasts that were phenotypically converted from cardiac fibroblasts were shown to regulate conduction velocity in infarcted hearts [33,34]. Therefore, we analyzed whether ADSC transplantation changed the expression of myofibroblasts in the infarcted hearts.…”

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

“…CFs form N-cadherin-mediated interactions with CMs, which influences CM structure and contractility during development, normal function and disease (Chopra et al, 2011;Kudo-Sakamoto et al, 2014;Vreeker et al, 2014). In a recent study, N-cadherin bonds between CFs and CMs were shown to dynamically deform CM membranes in response to MyoFB contraction and induce a measurable slowing of CM conduction velocity (Thompson et al, 2014). This study demonstrates a mechanical signal from MyoFBs that affects the electrophysiology of CMs and may contribute to risk of arrhythmia and other cardiovascular conditions that are associated with low conduction velocity (King et al, 2013).…”

Mechanical signaling coordinates the embryonic heartbeat

“…Mechanical stimulation of the substrate in cultured embryonic chick CMs with 6% stretch excites quiescent myocytes (39). Mechanical stress exerted by fibroblasts affects the wave front velocity of neonatal rat CMs (40,41), and neonatal and adult rat CMs cultured in similar conditions exhibit mechanical stimulation and entrainment (42). In some of these experiments, it is known that stretchinduced activation involves cardiac ryanodine receptors (9).…”