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

Abstract

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

ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro

“…Consistent with reported studies [20][21][22][23] , we determined that H 2 O 2 induced apoptosis in MSCs, which was shown by the activation of caspase 3 and cleavage of poly-ADP-ribose polymerase (PARP) (Figure 2), positive Annexin V staining ( Figure 3B) and suppression of cytotoxicity by the pan-caspase inhibitor z-VAD ( Figure 3A, 3B).…”

“…Recent studies demonstrate that there is increased oxidative stress and decreased production of nitric oxide in the corpora cavernosa [18,19] . Reactive oxygen species (ROS) are toxic to transplanted stem cells, and the induction of apoptosis underlies the major mechanism of ROS-induced cytotoxicity [20][21][22][23] . Meanwhile, ROS can also activate autophagy in certain conditions [24][25][26] .…”

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

“…24). TXN2 regulates cellular redox state and survival by suppressing mitochondrial ROS generation and by inhibiting apoptosis stress kinase-1-dependent apoptotic signaling (16). TXRD2 was shown to play a crucial role during postischemic reperfusion via thiol regeneration (15).…”

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis

“…To explore a therapeutic effect of the ASK1 inhibitor in treatment of ovarian caner, ID8 tumor-bearing mice were treated with GS444217 in a chow diet, as we performed previously (35). Phenotype analyses showed that GS444217 markedly attenuated accumulation of ascites fluid, tumor growth, and peritoneal implantations ( Figure 7, A-D).…”