Cardiac gap junction remodeling by stretch: is it a good thing?

Abstract

Cardiac cells contract and are also normally exposed to the mechanical events in their surroundings. It is now well established that both cardiac gene expression and protein synthesis are subject to regulation by mechanical forces, including stretch. For example, mechanical stretch is known to be one of the most important stimuli leading to cardiac hypertrophy,1–5 and recent studies indicate that cardiac myocyte hypertrophy is stimulated in vitro by specific directions and degrees of stretch.6 Similarly, certain stretchsensitive sarcolemmal ion channels and exchangers have been found in cardiac myocytes7 and have been implicated in the mechanism of stretch-induced arrhythmias.8 However, whereas signal transduction induced by mechanical stretch involves activation of a wide variety of second messenger systems,9 it remains to be determined which molecules are directly affected by stretch and which are the processes whereby mechanical stimuli trigger intracellular signaling pathways to activate protein kinase cascades and produce changes in function. The process of filling and ejecting blood subjects the cells of the heart to repetitive pulsatile stress. Our understanding of the basic electrophysiology underlying the cardiac action potential and its propagation across cells is largely on the basis of patch clamp data and isolated tissue experiments in the absence of mechanical stress. On the other hand, wholeheart electrophysiological mapping studies are often carried out in in situ functioning hearts. In either case, the role of mechanical stress in impulse initiation and propagation has not been adequately addressed. In addition, although stretch is thought to play an important role in cardiac remodeling that is associated with heart failure, very little is known about its role in normal electrical function. The study by Zhuang et al10 in this issue of Circulation Research, which is the result of a successful collaboration between two outstanding laboratories, sheds new light on this important subject by detailing some of the electrophysiological consequences of mechanical stretch. The responses to uniform pulsatile and static stress were investigated using an innovative approach developed in the laboratory of Dr André Kléber. Previously, Dr Kléber and his colleagues used cell cultures grown in specific shapes to study the role of tissue geometry and cellular coupling on impulse propagation.11,12 These studies have led to a better understanding of the effects of source-sink mismatching during impulse propagation. In the present study, cultured rat neonatal myocytes were grown on a flexible foundation constructed of thin silicone rubber. Once the cells were firmly attached to this surface, the edges of the silicone were connected to a mechanical device that would deform the silicone base in a controlled fashion. Using this system, various stretch protocols were applied along one or two axes for a predetermined amount of time. This approach provided a reliable source of cells that have been subjected to similar and reproducible stretch protocols. Multiple-site optical mapping of voltage-dependent fluorescence was performed to assess the effects of pulsatile stretch on propagation and upstroke velocity. The authors hypothesized that pulsatile stretch would produce an immediate adaptive response that would affect conduction parameters, and this is exactly what they found. Measurements of conduction velocity from cells subjected to pulsatile stress demonstrated a modest increase in propagation velocity compared with control cells. These effects were observed within the first hour of pulsatile stretch and continued over the next 6 hours. The upstroke velocity of the action potential did not change significantly at any of the time points measured, which suggested that pulsatile stretch did not affect the active membrane currents involved in cardiac excitation. Next, the authors hypothesized that the electrophysiological changes were the result of an alteration in the expression of proteins integrally involved in propagation of the electrical impulse. One of the important parameters involved in determining how fast action potentials propagate through cardiac tissue is intercellular coupling. The cells in the heart are electrically and metabolically coupled through gap junction channels. These channels provide a low-resistance pathway, which allows the excitation current to spread throughout the heart. Over the last 12 years, the laboratory of Dr Jeffery Saffitz has pioneered the study of connexins in normal and diseased heart tissues using immunohistochemistry.13–15 With this approach, the effects of pulsatile stretch on the expression of the major ventricular gap junction protein, connexin43 (Cx43), as well as the fascia adherens junction protein N-cadherin, were determined. Previously, Wang et al16 reported that 4 hours of pulsatile stretch of cultured rat myocytes caused a 3-fold increase in Cx43 levels. In the study by Zhuang et al,10 stretch also caused a significant increase in the amount of Cx43 immunoreactive signal. However, this change occurred after 1 hour of pulsatile The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY. Correspondence to José Jalife, MD, Department of Pharmacology, SUNY Upstate Medical University, 766 Irving Ave, Syracuse, NY 13210. E-mail jalifej@upstate.edu (Circ Res. 2000;87:272-274.) © 2000 American Heart Association, Inc.

Cite this paper

@article{Morley2000CardiacGJ, title={Cardiac gap junction remodeling by stretch: is it a good thing?}, author={G E Morley and Jos{\'e} Jalife}, journal={Circulation research}, year={2000}, volume={87 4}, pages={272-4} }