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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #340601

Research Project: Nutritional Metabolism in Mothers, Infants, and Children

Location: Children's Nutrition Research Center

Title: Cardiac-specific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure

item DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC)
item WANG, QIONGLING - Baylor College Of Medicine
item MONROE, TANNER - Baylor College Of Medicine
item YU, HAN - Children'S Nutrition Research Center (CNRC)
item Nakata, Paul
item HIRSCHI, KENDAL - Children'S Nutrition Research Center (CNRC)
item WANG, JIN - Children'S Nutrition Research Center (CNRC)
item RODNEY, GEORGE - Baylor College Of Medicine
item WEHRENS, XANDER - Baylor College Of Medicine
item CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC)

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/20/2017
Publication Date: 4/4/2017
Citation: Donelson, J., Wang, Q., Monroe, T.O., Yu, H., Nakata, P.A., Hirschi, K.D., Wang, J., Rodney, G.G., Wehrens, X., Cheng, N. 2017. Cardiac-specific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure [abstract]. Cardiovascular Research Institute (CVRI) Symposium, April 4, 2017, Baylor College of Medicine, Houston, TX. p. 34.

Interpretive Summary:

Technical Abstract: Experimental and clinical investigations have demonstrated that reactive oxygen species (ROS) production is increased during cardiac hypertrophy and heart failure. Excess ROS can directly impair cardiac contraction through modification of Ca2+ handling proteins or activate multiple effectors and signaling pathways to reprogram fetal gene expression involved in the progression of cardiac hypertrophy and eventual heart failure. Both NADPH oxidase and mitochondrial derived ROS are contributing factors to the pathological conditions. However, pharmacological strategies targeting either NADPH oxidases or mitochondrial ROS pathways to ameliorate oxidative stress in heart failure have not been successful. Therefore, better elucidation of the mechanisms underlying the effect of ROS and identification of factors in regulating NADPH oxidases and mitochondrial ROS pathways will offer insight into novel therapeutic targets for treatment of heart failure in patients. Several lines of evidence demonstrate that Grx3 may have critical functions in regulating stress-mediated signaling pathways. Most importantly, recent studies revealed that forced expression of Grx3 in transgenic mice (heart) could enhance cardiomyocyte contractility and modulate calcineurin-NFAT-mediated signaling and PKC activity in the progression of pressure-overload induced heart hypertrophy. To study the function of Grx3 on cardiac hypertrophy in vivo, a mouse Grx3 conditional allele with two LoxP sites flanking exon2 was created and cardiac specific Grx3 deficient (CKO) mice were generated by crossing with alpha-MHC-cre mice. Single cardiomyocytes were isolated from Grx3 KO and control hearts to study the function of Grx3 in regulating ROS production. Expression of Grx3 was decreased in aged hearts from wild-type mice. Mice with cardiac specific deletion of Grx3 deletion are viable and grew indistinguishably from their littermates, with no difference in either body or heart weight at 3 months of age. No difference in cardiac function was found between Grx3 CKO mice and littermate controls at this age. However, at the age of 12 months, Grx3 CKO mice displayed left ventricular hypertrophy with a significant decrease in ejection fraction and fractional shortening that was associated with increased expression of markers for heart failure. ROS production, revealed by DHE staining, was significantly increased in Grx3 CKO cardiomyocytes compared to control cells. Furthermore, deletion of Grx3 impaired Ca2+ handling in cardiomyocytes. These findings support the hypothesis that Grx3 is an important factor in regulating cardiac hypertrophy by controlling cellular redox homeostasis and Ca2+ handling in the heart.