Vascular transcriptome landscape of Trail-/- mice: Implications and therapeutic strategies for diabetic vascular
Siân P Cartland1,2, Ruby C Y Lin2,3,4, Scott Genner1
1Heart Research Institute, Sydney, NSW, Australia.
Abstract:
Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome-wide transcriptome of aortic tissue from Trail-/- versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses showed many of these genes were related to inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation. We identified vascular protective and pathological gene clusters, with Ifi205 as the most significantly reduced vascular protective gene, whereas Glut1, the most significantly increased pathological gene with TRAIL deletion. We hypothesized that therapeutic targets could be devised from such integrated analysis and validated our findings from vascular tissues of diabetic mice. From the differentially expressed gene targets, enriched transcription factor (TF) and microRNA binding motifs were identified. The top two TFs were Elk1 and Sp1, with enrichment to eight gene targets common to both. miR-520d-3p and miR-377-3p were the top enriched microRNAs with TRAIL deletion; with four overlapping genes enriched for both microRNAs. Our findings offer an alternate in silico approach for therapeutic target identification and present a deeper understanding of gene signatures and pathways altered with TRAIL suppression in the vasculature.
Insights
Suppressed levels of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) impact vascular health. TRAIL deletion alters gene expression, revealing potential therapeutic targets for vascular metabolic diseases.
Area of Science:
- Vascular Biology
- Genomics
- Metabolic Diseases
Background:
- Circulating plasma levels of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are reduced in patients with cardiovascular and diabetic diseases.
- TRAIL plays a role in regulating vascular homeostasis and metabolic function.
Purpose of the Study:
- To identify novel therapeutic targets for vascular metabolic diseases by analyzing gene expression changes following TRAIL deletion.
- To understand the molecular mechanisms underlying vascular dysfunction in the absence of TRAIL.
Main Methods:
- Genome-wide transcriptome analysis of aortic tissue from TRAIL-deficient (Trail-/-) and wild-type (Trail+/+) mice.
- Gene enrichment analysis to identify biological pathways and gene clusters affected by TRAIL deletion.
- In silico identification of transcription factor (TF) and microRNA binding motifs associated with differentially expressed genes.
Main Results:
- TRAIL deletion resulted in 861 differentially expressed genes in aortic tissue.
- Key affected pathways included inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation.
- Ifi205 was identified as a significantly reduced protective gene, while Glut1 was identified as a significantly increased pathological gene.
- Elk1 and Sp1 were top enriched TFs, and miR-520d-3p and miR-377-3p were top enriched microRNAs.
Conclusions:
- Integrated in silico analysis of transcriptome data provides a novel approach for identifying therapeutic targets in vascular metabolic diseases.
- TRAIL suppression significantly alters vascular gene expression, impacting protective and pathological pathways.
- Findings deepen the understanding of gene signatures and molecular mechanisms associated with TRAIL deficiency in the vasculature.
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