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Title: Transcriptome analysis re1.eals the role of glutaredoxin 3 in cardiac energy metabolism in obese mice

Author
item CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC)
item DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC)
item YU, HAN - Arkansas Children'S Nutrition Research Center (ACNC)
item WANG, QIONGLING - Baylor College Of Medicine
item MO, QIANXING - Baylor College Of Medicine
item LI, NA - Baylor College Of Medicine
item SUN, QIN - Baylor College Of Medicine
item Nakata, Paul
item RODNEY, GEORGE - Baylor College Of Medicine
item WEHRENS, XANDER - Baylor College Of Medicine

Submitted to: Workshop Proceedings
Publication Type: Proceedings
Publication Acceptance Date: 3/21/2018
Publication Date: 4/10/2018
Citation: Cheng, N., Donelson, J., Yu, H., Wang, Q., Mo, Q., Li, N., Sun, Q., Nakata, P.A., Rodney, G.G., Wehrens, X.H. 2018. Transcriptome analysis re1.eals the role of glutaredoxin 3 in cardiac energy metabolism in obese mice. Baylor College of Medicine, Cardiovascular Research Institute, Sixth Annual Symposium, April 10th, 2018, Houston, Texas.

Interpretive Summary:

Technical Abstract: Obesity has been considered an independent risk factor for many cardiovascular diseases (CVD) including heart failure. Recent epidemiological studies; however, implicate that heart failure patients with mild obesity have a better prognosis than their leaner counterparts . The underlying mechanism(s) that explain(s) this obesity paradox remains to be elucidated. Obesity is often associated with oxidati.e stress that is considered as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of major antioxidant systems in the heart. Grx activity was found to be increased in both obese and diabetic animals/patients. Recent studies demonstrated that upregulation of Grx1 could pre.ent cardiac complications in mice with type1 diabetes. Grx3 is a monothiol Grx that contains a Trx-like domain and two tandem Grx domains along with a number of unique features not present in other classical Trxs and Grxs. Se.eral lines of evidence demonstrate that Grx3 acts as a negati.e regulator of cardiac hypertrophy . Our previous studies also demonstrate that Grx3 is critical for protecting cells from oxidati.e stress. However, the metabolic impact of Grx3 on cardiac function in diet-induced obese (DIO) hearts has not been fully explored. In this study , we employ a transcriptome approach to in.estigate the effect of Grx3 on cardiac energy metabolism in the hearts of DIO mice. To study the function of Grx3 on cardiac energy metabolism we first created a Grx3 conditional allele mouse. Grx3 cardiac specific deficient (CKO) mice were then generated by crossing the Grx3 conditional allele mouse with an alpha-MHC-cre mouse. A genome-wide transcriptional profiling was conducted by DNA microarray analysis. Grx3 protein le.els, but not mRNA le.els, were significantly increased in the hearts of mice fed with high fat diet compared to mice fed with chow diet. After being fed with high fat diet for 8 months, both CKO mice and their littermates became obese with no distinguishable difference in either body or heart weight. However, echocardiographic analysis demonstrated that CKO DIO mice displayed left .entricular systolic dysfunction with a significant decrease in ejection fraction and fractional shortening. ROS production, revealed by DHE staining, was significantly increased in Grx3 CKO cardiomyocytes compared to control cells. Transcriptional profiling of gene expression in CKO and control hearts of DIO mice revealed a significant down-regulation of PPAR pathway and mitochondria genes. Furthermore, biochemical and cellular metabolic analysis indicated that disruption of Grx3 impaired mitochondrial bioenergetics. These findings support the hypothesis that Grx3 is an important factor in regulating cardiac energy metabolism by controlling cellular redox homeostasis and modulating mitochondrial bioenergetics in the heart.