Journal
CIRCULATION
Volume 136, Issue 23, Pages 2271-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.117.030972
Keywords
angiotensin II; aortic aneurysm, abdominal; 3-hydroxyanthranilic acid; indoleamine-pyrrole 2,3-dioxygenase; matrix metallopeptidases; tryptophan
Funding
- National Institutes of Health [HL079584, HL080499, HL089920, HL110488, HL128014, HL132500, HL137371, HL140954, AG047776, CA213022]
- Georgia Research Alliance
- Youth Top-Notch Talent Support Program in China
- Youth Yangtze River Scholar Program in China
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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-kappa B. 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.
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