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Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology
Author(s) -
Joca Humberto C.,
Coleman Andrew K.,
Ward Chris W.,
Williams George S. B.
Publication year - 2019
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp277083
Subject(s) - mechanotransduction , nadph oxidase , reactive oxygen species , calcium signaling , microbiology and biotechnology , microtubule , calcium in biology , calcium , chemistry , sodium calcium exchanger , oxidative stress , signal transduction , biophysics , biology , intracellular , biochemistry , organic chemistry
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.Abstract 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 (Ca 2+ ) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca 2+ release and arrhythmia. Here, we expanded our existing computational models of Ca 2+ 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 Ca 2+ release dynamics (i.e. Ca 2+ sparks and Ca 2+ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X‐ROS can prevent Ca 2+ ‐dependent arrhythmias.