Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo

Abstract

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.

Indoleamine 2 3-dioxygenase knockout limits angiotensin II-induced aneurysm in low density lipoprotein receptor-deficient mice fed with high fat diet

“…Aneurysm formation was associated with an accumulation of macrophages and T lymphocytes within the adventitia and the media, but no significant differences were observed between AngII-infused Ldlr -/- Ido1 +/+ and Ldlr -/- Ido1 -/- mice ( Fig 2A and 2B ). A recent study reported that IDO promoted aneurysm formation through 3HAA production, which activated MMP2 expression[ 12 ]. Therefore, we investigated MMP expression and activity in our model.…”

“…Angiotensin (Ang) II, widely used to induce dissecting aortic aneurysm [ 10 ], was previously shown to increase IDO activity through the production of mitochondrial reactive oxygen species [ 11 ]. Moreover, a recent report indicates that IDO deficiency in AngII-infused apolipoprotein e-deficient ( Apoe -/- ) mice protects against AAA[ 12 ]. The authors attributed the pro-aneurysmal effect of IDO to one of the Kyn-derived metabolites, 3-hydroxyanthranilic acid (3-HAA), which induced aneurysm by increasing MMP-2 expression in VSMC[ 12 ].…”

“…Moreover, a recent report indicates that IDO deficiency in AngII-infused apolipoprotein e-deficient ( Apoe -/- ) mice protects against AAA[ 12 ]. The authors attributed the pro-aneurysmal effect of IDO to one of the Kyn-derived metabolites, 3-hydroxyanthranilic acid (3-HAA), which induced aneurysm by increasing MMP-2 expression in VSMC[ 12 ].…”

Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR‐181b/SIRT1/HO‐1 signaling

“…The maximal outer diameter of the suprarenal aorta was measured by the ImageJ software (Wayne Rasband, National Institutes of Health, Bethesda, MD). An aneurysm was defined as ≥50% dilation of the outer diameter, as compared to the suprarenal aortae of mice in the control group (Q. Wang et al, ). AAA formation was classified into four types, as described by Daugherty, Cassis, and Lu (): Type I is a small, single dilation that is 1.5–2.0 times greater than normal; Type II is a large, single dilation that is more than 2.0 times larger than normal diameter; Type III is multiple dilations; and Type IV is an aortic rupture that results in death due to bleeding into the peritoneal cavity.…”

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…IDO is a unique immune checkpoint protein by promoting tryptophan degradation via the kynurenine pathway and can be blocked using small molecule inhibitors. By converting tryptophan to kynurenine, IDO promotes immune suppression via two distinctive molecular mechanisms, 1) depletion of an essential amino acid, tryptophan, to activate cellular stress pathways via GCN2 [50] and 2) generating downstream immune suppressive metabolites such as 3hydroxyanthranillic acid [51] and xanthurenic acid [52]. Details of these mechanisms are extensively discussed in reviews [53]; thus we will not discuss this further due to the space limitation.…”