Vascular transcriptome landscape of Trail -/- mice: Implications and therapeutic strategies for diabetic vascular disease.

Autor: Cartland SP; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Lin RCY; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.; Westmead Institute for Medical Research, Sydney, NSW, Australia., Genner S; Heart Research Institute, Sydney, NSW, Australia., Patil MS; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Martínez GJ; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Westmead Institute for Medical Research, Sydney, NSW, Australia.; División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago, Chile.; Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago, Chile., Barraclough JY; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Gloss B; Westmead Institute for Medical Research, Sydney, NSW, Australia., Misra A; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Patel S; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Kavurma MM; Heart Research Institute, Sydney, NSW, Australia.; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Jul; Vol. 34 (7), pp. 9547-9562. Date of Electronic Publication: 2020 Jun 05.
DOI: 10.1096/fj.201902785R
Abstrakt: 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.
(© 2020 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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