Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology
JournalJournal of Physiology
MetadataShow full item record
Abstract Key Points:
* Our group previously discovered and characterized the microtubule mechanotransduction pathway linking diastolic stretch to NADPH oxidase 2-derived reactive oxygen species signals that regulate calcium sparks and calcium influx pathways.
* Here we used focused experimental tests to constrain and expand our existing computational models of calcium signalling in heart.
* Mechanistic and quantitative modelling revealed new insights in disease including: changes in microtubule network density and properties, elevated NOX2 expression, altered calcium release dynamics, how NADPH oxidase 2 is activated by and responds to stretch, and finally the degree to which normalizing mechano-activated reactive oxygen species signals can prevent calcium-dependent arrhythmias.
Microtubule (MT) mechanotransduction links diastolic stretch to generation of NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS), signals we term X-ROS. While stretch-elicited X-ROS primes intracellular calcium (Ca2+) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca2+ release and arrhythmia. Here, we expanded our existing computational models of Ca2+ signalling in heart to include MT-dependent mechanotransduction through X-ROS. Informed by new focused experimental tests to properly constrain our model, we quantify the role of X-ROS on excitation-contraction coupling in healthy and pathological conditions. This approach allowed for a mechanistic investigation that revealed new insights into X-ROS signalling in disease including changes in MT network density and post-translational modifications (PTMs), elevated NOX2 expression, altered Ca2+ release dynamics (i.e. Ca2+ sparks and Ca2+ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X-ROS can prevent Ca2+-dependent arrhythmias. Copyright 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
Excitation Contraction Coupling
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85060637385&doi=10.1113%2fJP277083&partnerID=40&md5=3d87727fcf93d67d20d884c91975aea8; http://hdl.handle.net/10713/8566