Mathematical simulations of sphingosine-1-phosphate actions on mammalian ventricular myofibroblasts and myocytes

MacCannell, K.A., Chilton, L., Smith, G.L., and Giles, W.R. (2015) Mathematical simulations of sphingosine-1-phosphate actions on mammalian ventricular myofibroblasts and myocytes. In: Dixon, Ian M.C., and Wigle, Jeffrey T., (eds.) Cardiac Fibrosis and Heart Failure: cause or effect? Advances in Biochemistry in Health and Disease (13). Springer, Cham, Switzerland, pp. 299-322.

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Mathematical modeling has been used to explore the consequences of the actions of sphingosine-1-phosphate (S-1-P) within the ventricular myocardium. Electrophysiological data obtained from rabbit cultured myofibroblasts (Chilton et al. 2007) provided the basis for modifications of our model of electrotonic coupling between ventricular myocytes and fibroblasts (MacCannell et al. 2007). Specifically, an in silico fibroblast/myocyte hybrid model was modified to account for the electrophysiological properties that are characteristic of the myofibroblast (the wound healing phenotype of the fibroblast). In addition, equations describing an S-1-P-induced current that can be activated in the myofibroblast were added.

The sets of simulations that constitute this paper demonstrate that S-1-P can cause a significant depolarization of the resting membrane potential in both the myofibroblast and myocyte. When the myocyte to fibroblast coupling ratio is 1:1, this concentration-dependent effect is due to ligand-gated current in the myofibroblast depolrizing the myocyte through heterotypic connexin-mediated intercellular junctions. In addition to changing the resting potential in the myocyte, the S-1-P induced current resulted in significant changes in action potential waveform.

A second set of simulations was done for the purpose of exploring the effects of S-1-P on myocytes that have some of the main electrophysiological properties of those from the failing heart. In these computations, the ten Tusscher model of the human ventricular myocyte was modified by reducing parameters as follows: cell capacitance, inward rectifier K+ current, delayed-rectifier K+ currents (IKs and IKr), and transient outward K+ current. In combination, these changes (each of which is associated with heart failure), resulted in prolongation of action potential duration. Simulations of electrotonic coupling between this 'failing' myocyte and myofibroblasts demonstrated that the resting potential and APD in the failing myocyte is more susceptible to modulation by electrotonic influences from S-1-P-stimulated myofibroblasts when a 'failing' electrophysiological phenotype is mimicked.

In summary, our simulations draw attention to important effects of S-1-P on the ventricular myocardium even when this paracrine substance actos only on the fibroblast cell population. These cell-specific S-1-P effects alter the myocyte action potential via electrotonic coupling with myocytes. It is apparent that myofibroblasts can have significant effects on myocyte action potentials; and these effects would be expected to be more pronounced in the presence of ligand-gated effects on the myofibroblast. The general setting that we have attempted to replicate with this first order model has some similarities to acute or sterile inflammation in the myocardium wherein S-1-P concentrations in the interstitium are relatively high.

Item ID: 40655
Item Type: Book Chapter (Research - B1)
ISBN: 978-3-319-17436-5
Keywords: sphingosine-1-phosphate, electrotonic coupling, myocyte, fibroblast, myofibroblast, mathematical simulations
Funders: Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada, Alberta Heritage Foundation for Medical Research, British Heart Foundation (BHF)
Date Deposited: 16 May 2016 03:01
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 40%
06 BIOLOGICAL SCIENCES > 0606 Physiology > 060601 Animal Physiology - Biophysics @ 60%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 70%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 30%
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