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

Authors

Ninghui Cheng
Qianxing Mo
Jimmonique Donelson
Lingfei Wang
Ghislain Breton
George G Rodney
Jin Wang
Kendal D Hirschi
Xander H T Wehrens
Paul A Nakata

Publication Date

1-1-2021

Journal

International Journal of Biological Sciences

DOI

10.7150/ijbs.60263

PMID

34345213

PMCID

PMC8326124

PubMedCentral® Posted Date

7-13-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Cardiomegaly, Diet, High-Fat, Energy Metabolism, Fatty Acids, Gene Expression Profiling, Glutaredoxins, Heart Failure, Male, Mice, Mice, Knockout, Mice, Obese, Myocytes, Cardiac, Obesity, Oxidation-Reduction, Oxidative Stress, Heart failure, glutaredoxin, oxidative stress, cardiac energy metabolism, transcriptome

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.