Understanding the progression of atherosclerosis through gene profiling and co-expression network analysis in Apobtm2SgyLdlrtm1Her double knockout mice

• Gene co-expression network (GCN) was constructed to understand the progression of murine atherosclerosis.
• Maximum changes in gene expression was observed at early stages of disease.
• Genes associated with autophagy, ER stress, inflammation and neurotransmission were differentially expressed at early developmental stage
• These pathways could be the danger signals which can be associated with an ongoing disease process.
• Understanding these genes and associated pathways can help in developing better diagnostic and therapeutic targets for atherosclerosis.

The objective of the study was to gain molecular insights into the progression of atherosclerosis in Apobtm2SgyLdlrtm1Her mice, using transcriptome profiles. Weighted gene co network analysis (WGCNA) and time course analysis using limma were used to study disease progression from 0 to 20 weeks. Five co-expression modules were identified by WGCNA using the expression values of 2153 genes. Genes associated with autophagy, endoplasmic reticulum stress, inflammation and lipid metabolism were differentially expressed at early stages of atherosclerosis. Time course analysis highlighted activation of inflammatory gene signaling at 4 weeks, cell proliferation and calcification at 8 weeks, amyloid like structures and oxidative stress at 14 weeks and enhanced production of inflammatory cytokines at 20 weeks. Our results suggest that maximum gene perturbations occur during early atherosclerosis which could be the danger signals associated with subclinical disease. Understanding these genes and associated pathways can help in improvement of diagnostic and therapeutic targets for atherosclerosis.