Int J Biol Sci 2021; 17(11):2871-2883. doi:10.7150/ijbs.60263 This issue

Research Paper

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

Ninghui Cheng1✉, Qianxing Mo2, Jimmonique Donelson1, Lingfei Wang3, Ghislain Breton4, George G. Rodney5,6, Jin Wang3,7, Kendal D. Hirschi1, Xander H. T. Wehrens1,5,6, Paul A. Nakata1

1. USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
2. Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
3. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
4. Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
5. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
6. Cardiovascular Research Institute, and Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.
7. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Cheng N, Mo Q, Donelson J, Wang L, Breton G, Rodney GG, Wang J, Hirschi KD, Wehrens XHT, Nakata PA. Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis. Int J Biol Sci 2021; 17(11):2871-2883. doi:10.7150/ijbs.60263. Available from https://www.ijbs.com/v17p2871.htm

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Abstract

Graphic 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 transcripts 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 heart failure.

Keywords: Heart failure, glutaredoxin, oxidative stress, cardiac energy metabolism, transcriptome