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

  • Circulation. 2017 Dec 5;136(23):2271-2283. doi: 10.1161/CIRCULATIONAHA.117.030972.
Qiongxin Wang  1 ,  Ye Ding  2 ,  Ping Song  1 ,  Huaiping Zhu  1 ,  Imoh Okon  1 ,  Yang-Nan Ding  1 ,  Hou-Zao Chen  1 ,  De-Pei Liu  1 ,  Ming-Hui Zou  2
Affiliations
  • 1. Section of Molecular Medicine, Department of Medicine, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (Q.W., M.-H.Z.). Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., P.S., H.Z., I.O.,M.-H.Z.). State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.-N.D., H.C., D.L.).
  • 2. Section of Molecular Medicine, Department of Medicine, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (Q.W., M.-H.Z.). Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Y.D., P.S., H.Z., I.O.,M.-H.Z.). State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.-N.D., H.C., D.L.). [email protected] [email protected].
PMID: 28978552 DOI: 10.1161/CIRCULATIONAHA.117.030972
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 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.

Keywords
3-hydroxyanthranilic acid; angiotensin II; aortic aneurysm, abdominal; indoleamine-pyrrole 2,3-dioxygenase; matrix metallopeptidases; tryptophan.
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