Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo
| Autor: | De-Pei Liu, Ming-Hui Zou, Qiongxin Wang, Yang-Nan Ding, Huaiping Zhu, Hou-Zao Chen, Ping Song, Ye Ding, Imoh Okon |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Time Factors Genotype Hydrolases Mice Knockout ApoE 3-Hydroxyanthranilic Acid Myocytes Smooth Muscle 030204 cardiovascular system & hematology Pharmacology Muscle Smooth Vascular Article Interferon-gamma 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Physiology (medical) Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Medicine Aorta Abdominal Amino acid metabolism 3-Hydroxyanthranilic acid Cells Cultured Bone Marrow Transplantation business.industry Vascular disease Angiotensin II NF-kappa B Tryptophan Tryptophan Metabolism Elastic Tissue medicine.disease Abdominal aortic aneurysm Disease Models Animal Phenotype 030104 developmental biology chemistry Immunology Matrix Metalloproteinase 2 Cardiology and Cardiovascular Medicine business Aortic Aneurysm Abdominal Dilatation Pathologic |
| Zdroj: | Circulation. 136:2271-2283 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.117.030972 |
| Popis: | Background: Abnormal amino acid metabolism is associated with vascular disease. However, the causative link between dysregulated tryptophan metabolism and abdominal aortic aneurysm (AAA) is unknown. Methods: Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Mice with deficiencies in both apolipoprotein e (Apoe) and IDO (Apoe –/– /IDO –/– ) were generated by cross-breeding IDO –/– mice with Apoe –/– mice. Results: The acute infusion of angiotensin II markedly increased the incidence of AAA in Apoe –/– mice, but not in Apoe –/– /IDO –/– mice, which presented decreased elastic lamina degradation and aortic expansion. These features were not altered by the reconstitution of bone marrow cells from IDO +/+ mice. Moreover, angiotensin II infusion instigated interferon-γ, which induced the expression of IDO and kynureninase and increased 3-hydroxyanthranilic acid (3-HAA) levels in the plasma and aortas of Apoe –/– mice, but not in IDO –/– mice. Both IDO and kynureninase controlled the production of 3-HAA in vascular smooth muscle cells. 3-HAA upregulated matrix metallopeptidase 2 via transcription factor nuclear factor-κB. Furthermore, kynureninase knockdown in mice restrained 3-HAA, matrix metallopeptidase 2, and resultant AAA formation by angiotensin II infusion. Intraperitoneal injections of 3-HAA into Apoe –/– and Apoe –/– /IDO –/– mice for 6 weeks increased the expression and activity of matrix metallopeptidase 2 in aortas without affecting metabolic parameters. Finally, human AAA samples had stronger staining with the antibodies against 3-HAA, IDO, and kynureninase than those in adjacent nonaneurysmal aortic sections of human AAA samples. Conclusions: These data define a previously undescribed causative role for 3-HAA, which is a product of tryptophan metabolism, in AAA formation. Furthermore, these findings suggest that 3-HAA reduction may be a new target for treating cardiovascular diseases. |
| Databáze: | OpenAIRE |
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