Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation

Abstract

Aims: Inflammation and hypertension contribute to the progression of atherosclerotic aneurysm in the aorta. Vascular cell metabolism is regarded to modulate atherogenesis, but the metabolic alterations that occur in atherosclerotic aneurysm remain unknown. The present study aimed to identify metabolic pathways and metabolites in aneurysmal walls and examine their roles in atherogenesis. Methods: Gene expression using microarray and metabolite levels in the early atherosclerotic lesions and aneurysmal walls obtained from 42 patients undergoing aortic surgery were investigated (early lesion n =11, aneurysm n =35) and capillary electrophoresis–time-of-flight mass spectrometry (early lesion n =14, aneurysm n =38). Using immunohistochemistry, the protein expression and localization of the identified factors were examined (early lesion n =11, non-aneurysmal advanced lesion n =8, aneurysm n =11). The roles of the factors in atherogenesis were analyzed in macrophages derived from human peripheral blood mononuclear cells. Results: Enrichment analysis using 35 significantly upregulated genes (log2 ratio, ＞3) revealed the alteration of the kynurenine pathway. Metabolite levels of tryptophan, kynurenine, and quinolinic acid and the kynurenine-to-tryptophan ratio were increased in the aneurysmal walls. Gene and protein expression of kynureninase and kynurenine 3-monooxygenase were upregulated and localized in macrophages in the aneurysmal walls. The silencing of kynureninase in the cultured macrophages enhanced the expression of interleukin-6 and indoleamine 2,3-dioxygenase 1. Conclusion: Our study suggests the upregulation of the kynurenine pathway in macrophages in aortic atherosclerotic aneurysm. Kynureninase may negatively regulate inflammation via the kynurenine pathway itself in macrophages.

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

“…Consistently, reduced kynurenine production was shown to be associated with an increased inflammatory response in the lungs of aged individuals during an influenza infection [ 201 ]. Another study found kynurenine metabolism pathways were upregulated in the inflammatory disease, aortic atherosclerotic aneurysm, and the metabolism of kynurenines help downregulate inflammation [ 202 ]. With progression of the kynurenine metabolism pathways, tryptophan is ultimately broken down into small molecules such as NAD + , picolinic acid (PA), ATP, and CO 2 [ 72 ], which each having different roles in the anti-inflammatory function of macrophages.…”

The Footprint of Kynurenine Pathway in Cardiovascular Diseases

“…150 Similarly, kynureninase and KMO were upregulated in macrophages of aortic atherosclerotic aneurysm in patients who underwent aortic surgery. 152 Furthermore, 3-hydroxyanthranilic acid, in an NF-kB-dependent manner, increases the expression of matrix metalloproteinase 2 in VSMCs and accelerates the formation and exacerbation of Ang II-mediated abdominal aorta aneurysm in both Apoe −/− and Apoe −/− /IDO −/− mice. 150 Moreover, kynureninase knockdown strongly decreased 3-hydroxyanthranilic acid and matrix metalloproteinase 2 and partly prevented Ang II-mediated abdominal aorta aneurysm in mice.…”

Tryptophan: From Diet to Cardiovascular Diseases

“…In one study, silencing kynureninase, which was upregulated in macrophages in the aneurysmal walls in patient suffering from AAA, increased the expression of IL-6 and IDO in cultured macrophages, suggesting an anti-inflammatory effect of macrophage kynureninase [ 95 ]. In contrast to this study, another finding highlighted a role of the KP catabolite, 3-OHKyn, on EC apoptosis and dysfunction through the generation of superoxide anions by nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase [ 96 ].…”