背景:氨基酸代谢异常与血管疾病相关。然而,色氨酸代谢失调与腹主动脉瘤(AAA)之间的因果关系尚不清楚.
方法:吲哚胺2,3-双加氧酶(IDO)是色氨酸代谢犬尿氨酸途径中的第一个和限速酶。通过将IDO-/-小鼠与Apoe-/-小鼠杂交产生载脂蛋白e(Apoe)和IDO(Apoe-/-/IDO-/-)均缺乏的小鼠。
结果:急性输注血管紧张素II可显着增加Apoe-/-小鼠的AAA发生率,但在Apo-/-/IDO-/-小鼠中没有,表现为弹性椎板降解和主动脉扩张减少。来自IDO+/+小鼠的骨髓细胞的重建不会改变这些特征。此外,血管紧张素II输注引起的干扰素-γ,诱导了Apoe-/-小鼠血浆和主动脉中IDO和犬尿氨酸酶的表达,并增加了3-羟基邻氨基苯甲酸(3-HAA)水平,但不是在IDO-/-老鼠身上。IDO和犬尿氨酸酶都控制了血管平滑肌细胞中3-HAA的产生。3-HAA通过转录因子核因子-κB上调基质金属肽酶2。此外,小鼠犬尿氨酸酶抑制3-HAA,基质金属肽酶2,并通过血管紧张素II输注形成AAA。向Apoe-/-和Apoe-/-/IDO-/-小鼠腹膜内注射3-HAA持续6周可增加主动脉中基质金属肽酶2的表达和活性,而不影响代谢参数。最后,人AAA样品具有更强的抗3-HAA抗体染色,IDO,和犬尿氨酸酶比人类AAA样本的相邻非动脉瘤主动脉切片中的犬尿氨酸酶。
结论:这些数据定义了以前未描述的3-HAA的致病作用,这是色氨酸代谢的产物,形成AAA。此外,这些发现提示降低3-HAA可能是治疗心血管疾病的新靶点.
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.