Abstract 17258: Mitochondrial Redox Protein Thioredoxin 2 Is Essential for Preserving Cardiac Function
There is increasing support for the idea that excessive production of reactive oxygen species (ROS) contribute to the pathogenesis of cardiac dysfunction. Mitochondrial redox protein thioredoxin (Trx2) plays a pivotal role in maintaining mitochondrial redox state and keeping mitochondrial reactive oxygen species (ROS) in check. Since mice with global deletion of Trx2 is embryonic lethal, the role of Trx2 in pathogenesis of cardiac dysfunction has not been determined. In the present study, we have generated transgenic mice with a cardiac-specific deletion of Trx2 by the loxP-Cre system in which Trx2 deletion is induced by Cre recombinase driven under the alpha-MHC promoter (Trx2-cKO). Trx2-cKO mice develop a severe phenotype of hypertrophic cardiomyopathy with onset at 1 month of age and death around 3 months of age. The phenotypes include decreased cardiac function as measured by echocardiography, increased heart weight and size with reduced ventrical wall thickness. Ultrastructural analyses shows that Trx2-cKO heart contains enlarged cardiomyocytes with irregular sarcomeres within the myofibrils, swollen mitochondria with cristolysis, accumulation of excess collagen contributed to the loss of myocardium action potential and contractility. Protein analyses indicate that other antioxidant proteins TrxR2 and catalase exhibit compensatory increases, expression of Nox2 and Nox4 was dramatically upregulated in Trx2-cKO. Consistently, ROS production indicated by dihydroethidium staining and ROS-induced cell apoptotic signaling measured by TUNEL staining and Bax expression were significantly increased by the Trx2 deletion. These results suggest that cardiac-specific deletion of Trx2 causes mitochondrial dysfunction, upregulation of cytosolic ROS -generating enzymes Nox2/4 and subsequent ROS-dependent cell apoptosis, leading to cell death and cardiac hypertrophy. Therefore, mitochondrial redox protein Trx2 is essential for preserving cardiac function. Further mechanistic studies will understand how Trx2 preserve mitochondrial integrity and how mitochondrial dysfunction caused by Trx2 deletion couples Nox upregulation and cardiac hypertrophy.
- © 2010 by American Heart Association, Inc.