Abstract 18071: Whole Body Periodic Acceleration Prevents Cardiac Ischemic-Reperfusion Injury by Transcriptional Regulation of Diverse Cytoprotective Signaling Pathways
Background: Periodic acceleration (pGz) delivers sinusoidal inertial forces (~0.3 x g) along the spinal (z) axis which imparts modest increases in pulsatile shear stress. pGz improves functional recovery when delivered before or after various experimental injuries including cardiac arrest and MI, hemorrhagic shock,dystrophin deficiency cardiomyopathy, and more recently human heart failure. The molecular mechanisms are uncertain.
Methods: We therefore exposed adult C57BL/J mice (N=6-12/group) to 7 days of pGz (60 min/d, ƒ=480 cycles/min) of pGz or sham (same periodic oscillations but along the y axis) followed by global myocardial ischemia-reperfusion (I/R) for 40 min in a working isolated mouse heart model. Measurements included: LV systolic and diastolic function, mitochondrial (mt) function and reactive oxygen species (ROS) production and damage, and caspase activation. The effects of pGz upon ventricular gene expression were quantified by microarray (subset of results confirmed by RT-PCR).
Results: Pretreatment with pGz resulted in significant functional protection from I/R-induced systolic dysfunction measured as peak developed LV pressure (P=0.01), preload recruitable stroke (P=0.03), and +dP/dt (P=0.02), as well as diastolic dysfunction measured as tau (P=0.01), -dP/dt (P=0.04) and EDP-EDV slope (P=0.01). pGz maintained mitochondrial O2 consumption and complex I and III activity, reduced ROS-mediated damage to mt proteins (protein carbonyls, P=0.02), and reduced caspase-3 activation (P=0.03). Multiple genes and miRNAs were differentially regulated (≥ 2-fold, false discovery rate <0.20) by pGz, with significant upregulation of several established stress response genes and pathways that included heat shock proteins, FK506 binding protein, p21, and Bcl-2, as well as several individual genes and miRNAs whose functions are currently unknown.
Conclusions: We conclude that pGz acts at least in part to reduce myocardial injury via transcriptional regulation of ROS, Ca+2 handling, cellular stress, molecular chaperone, and protein homeostasis pathways. Its potential as a safe, non-invasive and practical therapy to modulate multiple pathways that attenuate myocardial injury and cell stress signaling merits further study. .
Author Disclosures: F.X. McGowan: None. D.J. Watson: None. A. Uryash: None. T. O,Malley: None. H. He: None. V.M. Nadkarni: None. R.A. Berg: None. J.A. Adams: Consultant/Advisory Board; Modest; Stock options < $5,000 for advisory board.
- © 2016 by American Heart Association, Inc.