TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE −/− mice
| Autor: | Yusuke Higashi, Siva Sankara Vara Prasad Sakamuri, Jalahalli M. Siddesha, Ulrich Siebenlist, Patrice Delafontaine, Bysani Chandrasekar, Sergiy Sukhanov |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Apolipoprotein E Chemokine medicine.medical_specialty Pathology Genotype Mice Knockout ApoE Lipoproteins Inflammation Article Proinflammatory cytokine Mice Necrosis 03 medical and health sciences Sex Factors Internal medicine medicine Animals Crosses Genetic Triglycerides Adaptor Proteins Signal Transducing Metalloproteinase biology Chemistry Cell adhesion molecule Tissue inhibitor of metalloproteinase Atherosclerosis Plaque Atherosclerotic Extracellular Matrix Mice Inbred C57BL CXCL1 030104 developmental biology Endocrinology biology.protein Female Collagen medicine.symptom Cardiology and Cardiovascular Medicine Gene Deletion |
| Zdroj: | Atherosclerosis. 252:153-160 |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/j.atherosclerosis.2016.05.029 |
| Popis: | Background and aims Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. Methods TRAF3IP2/ApoE double knockout ( DKO ) mice were generated by crossing TRAF3IP2 −/− and ApoE −/− mice. ApoE −/− mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR. Results The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE −/− mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor α, TNFα), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17). Conclusions TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases. |
| Databáze: | OpenAIRE |
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