Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function.
Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function.
复制标题
DOI：
10.1161/circulationaha.114.012725
复制
发表时间：
2015-03-24
期刊：
影响因子：
37.8
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Huang Q;Zhou HJ;Zhang H;Huang Y;Hinojosa-Kirschenbaum F;Fan P;Yao L;Belardinelli L;Tellides G;Giordano FJ;Budas GR;Min W
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. 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. 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.
