Abstract 18346: Transcriptional Characterization of Glo1 Knockdown and Transgenic Mouse Models Implies a Role in Cardiometabolic Diseases
Accumulation of advanced glycation end-products (AGEs) has been associated with atherosclerosis and diabetes. As the major detoxifying enzyme for AGE precursors, Glyoxalase 1 (Glo1) has been implicated in diabetic complications and more recently in coronary artery disease (CAD). We have recently identified Glo1 as a potential key regulator for an antigen-related gene network that is causal for CAD through an integrative genomics analysis. However, whether Glo1 plays a protective role against cardiometabolic disorders remains controversial. To systematically investigate the impact of Glo1, we performed genome-wide transcriptional profiling of two genetically modified animal models with either Glo1 overexpression in a transgenic (TG) model or Glo1 knockdown (KD), both on C57BL/6J background. For each mouse model, we examined the liver, aorta, adipose and kidney tissues. We found that the Glo1 KD mice which had ~50% reduced Glo1 expression showed much stronger perturbation at transcriptomic level, as compared to Glo1 TG mice. For Glo1 KD mice, significant differential expression was observed across tissues for multiple known cardiometabolic risk genes, including Ide, Cdkn2b and Col4a1, as well as perturbations of lipid metabolic pathways such as PPAR signaling and fatty acid metabolism. We also identified iron transport and collagen formation pathways as specifically enriched in the differentially expressed genes in aorta. When intersected with human GWAS, the Glo1 KD signature genes were found to be enriched for candidate genes associated with lipid levels, type 2 diabetes and coronary heart disease. Lastly, genes perturbed in the Glo1 KD animals had significant overlap with our predicted CAD-antigen gene network in both aorta (p = 0.005) and liver (p = 0.03). This study suggests a functional role of Glo1 in regulating multiple processes relevant to cardiometabolic diseases. Future investigation of these animal models in atherogenesis under diabetic conditions is warranted.
- Glyoxylase 1 (Glo1)
- Transcriptional profiling
- Glo1 knockdown mice
- Glo1 transgenic mice
- Cardiovascular disease
Author Disclosures: L. Shu: None. R.C. Davis: None. X. Wu: None. A.J. Lusis: None. A.A. Palmer: None. X. Yang: None.
- © 2015 by American Heart Association, Inc.