Abstract
The discrepancy of indoleamine 2, 3-dioxygenase 1 (IDO1) function in atherosclerosis has been noted. Compared to the protective effect of IDO1 against established atherogenesis, the role of IDO1 in the developmental process of atherosclerosis is still unclear. Here, the expression patterns and activities of IDO1 and its isoenzyme tryptophan 2,3-dioxygenase (TDO) in aortas and blood samples of patients with atherosclerosis were investigated. IDO1 and TDO were colocalized with CD3-positive lymphocytes and CD68-positive macrophages in atherosclerotic lesions. The expression and activity of IDO1 and TDO increased with the grade of the histological classification in early atherosclerosis (grade I, II), but the increase did not continue in advanced atherosclerosis (grade III). Treatment of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein (oxLDL) induced the expression of IDO1 via the PI3K/Akt/NF-κB pathway, indicating the potential function of IDO1 in foam cells. Before and after treatment with oxLDL on THP-M, IFN-γ-induced IDO1 exhibited different degrees of promotion on foaming, inflammatory factor production and cell apoptosis. Finally, we found that the IDO1 inhibitor 1-methyl-tryptophan could elevate the high-density lipoprotein cholesterol level in serum and reduce the area of the aortic atherosclerotic lesions in high-fat diet-fed ApoE−/− mice. Our study indicated that IDO1 played a complicated and unfixed role in the entire process of atherogenesis, despite the atheroprotective role in established atherosclerosis. IDO1 also had proatherosclerotic functions in the developmental stages of atherosclerosis. Modulation of IDO1 could be a good method for alleviating atherosclerosis.
Highlights
Atherosclerosis is an arterial disease involving progressive accumulation of cholesterol deposits and eventual buildup of plaque inside the arterial wall.[1]
IDO1 and TDO were expressed in atherosclerotic lesions and codistributed with CD3-positive lymphocytes and CD68-positive macrophages In the Tampere Vascular Study, IDO1 expression was observed in the macrophage cores of human atherosclerotic plaques.[26]
The IDO1 inhibitor 1-methyl tryptophan (1-MT) could ameliorate the development of atherogenesis in high-fat diet (HFD)-fed ApoE−/− mice For the in vivo assay, we investigated the potential effects of the IDO1 inhibitor 1-MT on preventing atherosclerotic lesion formation in ApoE−/− mice
Summary
Atherosclerosis is an arterial disease involving progressive accumulation of cholesterol deposits and eventual buildup of plaque inside the arterial wall.[1] Atherosclerosis is associated with inflammation, abnormal lipid metabolism, damage to the vascular endothelial structure and immune regulation.[2] The exact cause of atherosclerosis is not known, hypertension, diabetes, smoking, oxidized low-density lipoprotein (oxLDL) and so forth are known to be risk factors of atherosclerosis.[3,4,5] Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis.[6,7] During atherogenesis progression, circulating monocytes adhere to the intima and differentiate into macrophages that phagocytize oxLDL via scavenger receptors, thereby transforming into foam cells.[8] oxLDL can induce apoptosis,[9] inflammatory responses and phagocytosis of macrophages.[10,11,12]. The activated kynurenine pathway (KP) has been suggested to play an important role in atherogenesis. KP is the primary pathway of tryptophan (Trp) catabolism in most mammalian cells[13,14] and generates several bioactive catabolites, such as kynurenine (Kyn), anthranilic acid (AA), kynurenic acid (KA), 3-hydroxykynurenine
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