Crucial role of mammalian glutaredoxin 3 in cardiac energy metabolism in diet-induced obese mice revealed by transcriptome analysis

Authors: CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC); MO, QIANXING - Baylor College Of Medicine; DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC); WANG, LINGFEI - H Lee Moffitt Cancer Center; BRETON, GHISLAIN - Baylor College Of Medicine; RODNEY, GEORGE - University Of Texas Health Science Center; WANG, JIN - H Lee Moffitt Cancer Center; HIRSCHI, KENDAL - Children'S Nutrition Research Center (CNRC); WEHRENS, XANDER - Baylor College Of Medicine; Nakata, Paul

Submitted to: International Journal of Biological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2021
Publication Date: 7/13/2021
Citation: Cheng, N., Mo, Q., Donelson, J., Wang, L., Breton, G., Rodney, G.G., Wang, J., Hirschi, K.D., Wehrens, X., Nakata, P.A. 2021. Crucial role of mammalian glutaredoxin 3 in cardiac energy metabolism in diet-induced obese mice revealed by transcriptome analysis. International Journal of Biological Sciences. 17(11):2871-2883. https://doi.org/10.7150/ijbs.60263.
DOI: https://doi.org/10.7150/ijbs.60263

Interpretive Summary: Obesity is a known risk factor for cardiovascular disease. Oxidative stress may serve as a link between obesity and cardiovascular disease. 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. Previously, we showed a role for the glutaredoxin (GRX) 3 in protecting the heart from oxidative damage. In this study we extend this study by investigating the impact of GRX3 on the hearts of diet induced obese (DIO) mice. DIO mice which lacked a functional copy of the GRX3 gene in their hearts developed indistinguishable from control DIO mice when they were young but as they aged they displayed damage to their hearts. Biochemical measurements revealed that the DIO mice lacking a functional copy of the GRX3 gene had higher levels of reactive oxygen species in their hearts which can cause oxidative damage. Gene expression analysis showed that these mice had lower expression of genes associated with oxidation and fatty acid metabolism. Overall, our findings indicate that GRX3 may function in regulating oxidation in the heart. It is our hope that such information will help efforts to improve heart health in aging human populations.

Technical Abstract: Obesity is often associated with metabolic dysregulation and oxidative stress with the latter serving as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of the major antioxidant systems in the heart. Although Grx3 has been shown to act as an endogenous negative regulator of cardiac hypertrophy and heart failure, its metabolic impact on cardiac function in diet-induced obese (DIO) mice remains largely unknown. In the present study, analysis of Grx3 expression indicated that Grx3 protein levels, but not mRNA levels, were significantly increased in the hearts of DIO mice. Cardiac-specific Grx3 deletion (Grx3 CKO) mice were viable and grew indistinguishably from their littermates after being fed a high fat diet (HFD) for one month starting at 2 months of age. After being fed with a HFD for 8 months (starting at 2 months of age); however, Grx3 CKO DIO mice displayed left ventricular systolic dysfunction with a significant decrease in ejection fraction and fractional shortening that was associated with heart failure. ROS production was significantly increased in Grx3 CKO DIO cardiomyocytes compared to control cells. Gene expression analysis revealed a significant decline in the level of transcripts corresponding to genes associated with processes such as fatty acid uptake, mitochondrial fatty acid transport and oxidation, and citrate cycle in Grx3 CKO DIO mice compared to DIO controls. In contrast, an increase in the level of transcript corresponding to genes associated with glucose uptake and utilization were found in Grx3 CKO DIO mice compared to DIO controls. Taken together, these findings indicate that Grx3 may play a critical role in redox balance and as a metabolic switch in cardiomyocytes contributing to the development and progression of hearts failure.