Abstract
Objective Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. Methods The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis. TNK1 in mice aorta was measured by qPCR. The human CEA were obtained and identified as ruptured and stable plaques. The level of TNK1 was measured by qPCR and Western-blot staining. Further studies were conducted in THP-1 cells to explore the anti-inflammatory effects of TNK1. We induced the formation of macrophages by incubating THP-1 cells with PMA (phorbol 12-myristate 13-acetate). Afterwards, oxidized low-density lipoprotein (oxLDL) was used to stimulate the inflammation, and the secretion of inflammatory factors was measured by ELISA and qPCR. The levels of TNK1, total STAT1 and Tyk2, and the phosphorylation of STAT1 and Tyk2 were measured by western blot to uncover the mechanisms of TNK1. Results The oil red O staining indicated obvious deposition of lipid on the aorta of ApoE(-/-) mice after 8-week HFD treatment. The TNK1 level was much higher in both the HFD-fed ApoE(-/-) mice aorta arch and the ruptured human CEA plaques. We found that TNK1 was highly expressed in THP-1 cells, compared to other atherosclerotic related cells (HUVEC, HBMEC, and HA-VSMC), indicating TNK1 might be involved in the inflammation. Suppressing the expression of TNK1 by shTNK1 inhibited the oxLDL-induced secretion of inflammatory factors, such as IL-12, IL-6, and TNF-α. ShTNK1 also inhibited the uptake of lipid and decreased the cellular cholesterol content in THP-1 cells. Furthermore, the shTNK1 suppressed the oxLDL-induced phosphorylation of Tyk2 and STAT1. Conclusion TNK1 participated in the inflammation in atherosclerosis. shTNK1 suppressed the oxLDL-induced inflammation and lipid deposition in THP-1 cells. The mechanism might be related to the Tyk2/STAT signal pathway.
Highlights
Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations, such as coronary artery disease, and ischemic stroke [1]
We found a significant increase of tyrosine kinase nonreceptor 1 (TNK1) in the aorta of high-fat diet- (HFD-) fed ApoE(-/-) mice (5.78folds in HFD mice compared to normal fat diet mice) [9]
The present study found the upregulation of TNK1 in both HFD-fed ApoE(-/-) mice aorta and human ruptured plaques
Summary
Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations, such as coronary artery disease, and ischemic stroke [1]. The monocytes migrate from circulation to intima and change into macrophages. These macrophages secrete a large amount of proinflammatory factors, internalize lipid, Mediators of Inflammation and drive the hyperplasia of intima. The inhibition of the inflammation is an important strategy to prevent the progress of atherosclerosis. The Janus tyrosine kinase/signal transducers and activators of the transcription (JAK/STAT) pathway is a crucial signal pathway in inflammation [3]. It mediates the production of a large number of cytokines and growth factors. The activated STAT translocates to the cell nucleus and regulates the transcription of cytokines. Regulating the JAK/STAT pathway is a potential method for the inhibition of inflammation
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