Τρίτη 25 Δεκεμβρίου 2018

Quantitative Tests Reveal that Microtubules Tune the Healthy Heart but Underlie Arrhythmias in Pathology

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 signaling in heart. Mechanistic and quantitative modeling 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 (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+ signaling in heart to include MT‐dependent mechanotransduction through X‐ROS. Informed by new focused experimental tests to properly constrain our model, we quantitate 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 signaling in disease including: changes in MT network density and 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.

This article is protected by copyright. All rights reserved



from Physiology via xlomafota13 on Inoreader http://bit.ly/2T810SB
via IFTTT

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Σημείωση: Μόνο ένα μέλος αυτού του ιστολογίου μπορεί να αναρτήσει σχόλιο.