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.