Thioredoxin-2 Inhibits Mitochondrial Reactive Oxygen Species Generation and Apoptosis Stress Kinase-1 Activity to Maintain Cardiac Function

• DOI: 10.1161/circulationaha.114.012725
• Publication Date: 2015-01-28T02:57:47Z
• Authors: Qunhua Huang; Huanjiao Jenny Zhou; Haifeng Zhang; Yan Huang; Ford Hinojosa-Kir...; Peidong Fan; Lina Yao; Luiz Belardinelli; George Tellides; Frank J. Giordano; Grant R. Budas; Wang Min
• Keywords: ASK1; Dilated Cardiomyopathy; Mitochondrial ROS

Background— Thioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing reactive oxygen species generation inhibiting apoptosis stress kinase-1 (ASK1)–dependent apoptotic signaling. To date, the role of Trx2 system in heart failure pathogenesis has not been investigated. Methods Results— Western blot histological analysis revealed expression levels were reduced hearts from patients with dilated cardiomyopathy, concomitant increase ASK1 phosphorylation/activity. Cardiac-specific knockout mice develop spontaneous cardiomyopathy at 1 month age increased size, ventricular wall thickness, progressive decline left contractile function, resulting mortality due to ≈4 months age. The cardiac function observed cardiac-specific was accompanied disruption ultrastructure, membrane depolarization, generation, ATP production, correlating signaling cardiomyocyte apoptosis. Chronic administration highly selective inhibitor improved phenotype maladaptive remodeling significant reductions oxidative stress, apoptosis, fibrosis, failure. Cellular data Trx2-deficient cardiomyocytes demonstrated inhibition generation. Conclusions— Our support an essential for preserving production ASK1-dependent Inhibition represents promising therapeutic strategy treatment