Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo
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 (AngII) 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, AngII infusion instigated interferon (IFN)-γ, which induced the expression of IDO and kynureninase (KNU) and increased 3-hydroxyanthranilic acid (3-HAA) levels in the plasma and aortas of Apoe-/- mice, but not in IDO-/- mice. Both IDO and KNU controlled the production of 3-HAA in vascular smooth muscle cells. 3-HAA upregulated MMP2 via transcription factor nuclear factor-kappa B (NF-κB). Furthermore, KNU knockdown in mice restrained 3-HAA, matrix metallopeptidase (MMP)2, and resultant AAA formation by AngII infusion. Intra-peritoneal injections of 3-HAA into Apoe-/- and Apoe-/-/IDO-/- mice for 6 weeks increased the expression and activity of MMP2 in aortas without affecting metabolic parameters. Finally, human AAA samples had stronger staining with the antibodies against 3-HAA, IDO, and KNU 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.
- Received August 7, 2017.
- Revision received August 31, 2017.
- Accepted September 14, 2017.