| First Author | Wang Q | Year | 2017 |
| Journal | Circulation | Volume | 136 |
| Issue | 23 | Pages | 2271-2283 |
| PubMed ID | 28978552 | Mgi Jnum | J:271081 |
| Mgi Id | MGI:6279583 | Doi | 10.1161/CIRCULATIONAHA.117.030972 |
| Citation | Wang Q, et al. (2017) Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo. Circulation 136(23):2271-2283 |
| abstractText | 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-gamma, 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-kappaB. 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. |
