In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 136, No. suppl_1 ( 2017-11-14)
Abstract:
Exercise increases disease penetrance in arrhythmogenic cardiomyopathy (ACM). Yet, how exercise contributes to disease pathogenesis is unclear. Mitochondria potentiate reactive oxygen species (ROS) generation during exercise that are scavenged by antioxidants, such as thioredoxin-2 (Trx2). Here we tested if deficits in Trx2-based ROS buffering act as substrates for exercise-induced cardiac apoptosis in ACM. Homozygote Desmoglein-2 mutant mice ( Dsg2 mut/mut ) model ACM features, thus WT and Dsg2 mut/mut mice were enrolled in a 10 week swimming protocol to evaluate survival and post-effort cardiac function, ROS production by EPR, and mitochondrial ROS-gating protein levels. Survival rate after swimming was 91% (20/22) in WT, but only 60% (15/25) in Dsg2 mut/mut mice (p=0.008). Of the survivors, Dsg2 mut/mut mice displayed cardiac dysfunction (Ejection Fraction 57±4 vs 84±0.4% in WT; n≥14/cohort, P 〈 0.001) and increased bouts of non-sustained VT. Swimming augmented ROS emission in Dsg2 mut/mut right ventricles (RV) than in WT (25±3 vs 15±1 Gauss/total protein [G/tp]; P 〈 0.05) and amplified ROS release from Dsg2 mut/mut left ventricles (LV) (39±5 G/tp vs mutant RV; P 〈 0.05). Isolated mutant mitochondria showed reduced NADH generation and peroxiredoxin-3, Trx2 and Trx2 reductase (Trx2R) protein levels, with impaired Trx2R activity (all P 〈 0.05 vs WT in RV & LV). When mitochondria bound, Apoptosis-Inducing Factor (AIF) acts as a NADH oxidoreductase, yet upon oxidation, AIF translocates to the nucleus and initiates apoptosis. After exercise, Dsg2 mut/mut hearts displayed marked AIF nuclear and chromatin-bound protein levels and increased AIF immunostained nuclei vs WT. Additionally, direct H 2 O 2 exposure or Trx2 inhibition (by auranofin) in Dsg2 mut/mut embryonic stem-cell derived myocytes elevated AIF-nuclear translocation and apoptosis (via AnnexinV/PI FaCS analysis). Our study reveals a novel causal link between exercise-evoked cardiac redox imbalance and aberrant AIF-Trx2 signaling in ACM, which was associated with increased apoptosis, propensity of arrhythmias and sudden cardiac death. These findings offer a new targetable mechanism for preventing one of the most cited, yet poorly understood, pathological phenotypes (apoptosis) in ACM.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.136.suppl_1.24032
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1466401-X
