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

Authors: DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC); WANG, QIONGLING - Baylor College Of Medicine; MONROE, TANNER - Baylor College Of Medicine; JIANG, XIQIAN - Baylor College Of Medicine; ZHOU, JIANJIE - Tsinghua University; YU, HAN - Children'S Nutrition Research Center (CNRC); MO, QIANXING - Tsinghua University; SUN, QIN - H Lee Moffitt Cancer Center; MARINI, JUAN - Children'S Nutrition Research Center (CNRC); WANG, XINQUAN - Tsinghua University; Nakata, Paul; HIRSCHI, KENDAL - Children'S Nutrition Research Center (CNRC); WANG, JIN - Baylor College Of Medicine; RODNEY, GEORGE - Baylor College Of Medicine; WEHRENS, XANDER H - Children'S Nutrition Research Center (CNRC); CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC)

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/30/2019
Publication Date: 4/29/2019
Citation: Donelson, J., Wang, Q., Monroe, T.O., Jiang, X., Zhou, J., Yu, H., Mo, Q., Sun, Q., Marini, J.C., Wang, X., Nakata, P.A., Hirschi, K.D., Wang, J., Rodney, G.G., Wehrens, X.T., Cheng, N. 2019. Cardiac-specific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure. Physiological Reports. https://doi.org/10.14814/phy2.14071.

Interpretive Summary: Cardiovascular diseases are a leading cause of death especially in aging adults. Understanding why this is and what is needed to maintain a healthy heart would help in the design of strategies to prevent or maybe reverse some forms of heart damage. In this study we investigate the role of the glutaredoxin (GRX) 3 in protecting the heart from oxidative damage. Investigations into GRX 3 gene expression revealed that expression of this gene in the heart of mice decreased with increasing age. Knocking out expression of this gene did not seem to affect heart function or viability in growing mice. In aging mice; however, a lack of GRX expression resulted in an enlargement in heart size and a decrease in heart function. Taken together, our findings revealed the importance of GRX3 expression in regulating heart size and heart function in mice by modulating oxidative and reductive reactions in the heart cells. It is our hope that such information will help efforts to improve heart health in aging human populations.

Technical Abstract: Growing evidence suggests that redox sensitive proteins including glutaredoxins (Grxs) can protect cardiac muscle cells from oxidative stress-induced damage. Mammalian Grx3 has been shown to be critical in regulating cellular redox states. However, how Grx3 affects cardiac function by modulating ROS signaling remains unknown. In this study, we found that expression of Grx3 in the heart is decreased during aging. To assess the physiological role of Grx3 in the heart, we generated mice in which Grx3 was conditionally deleted in cardiomyocytes (Grx3 CKO mice). Grx3 CKO mice were viable and grew indistinguishably from their littermates at 3 months of age. No difference in cardiac function was found comparing Grx3 CKO mice and littermate controls at this age. However, by the age of 12 months, Grx3 CKO mice exhibited left ventricular hypertrophy with a significant decrease in ejection fraction and fractional shortening along with a significant increase of ROS production and cardiac fibrosis in cardiomyocytes compared to controls. Deletion of Grx3 impaired Ca2+ handling, caused enhanced SR calcium (Ca2+) leak and decreased SR Ca2+ uptake. Furthermore, enhanced ROS production and alteration of Ca2+ handling in cardiomyocytes occurred prior to cardiac dysfunction in young mice. Therefore, our findings demonstrate that Grx3 is an important factor in regulating cardiac hypertrophy and heart failure by modulating cellular redox homeostasis and Ca2+ handling in the heart.