APOC3 induces endothelial dysfunction through TNF-α and JAM-1

Abstract

BackgroundThe fatality rate for cardiovascular disease (CVD) has increased in recent years and higher levels of triglyceride have been shown to be an independent risk factor for atherosclerotic CVD. Dysfunction of endothelial cells (ECs) is also a key factor of CVD. APOC3 is an important molecule in lipid metabolism that is closely associated with hyperlipidemia and an increased risk of developing CVD. But the direct effects of APOC3 on ECs were still unknown. This study was aimed at determining the effects of APOC3 on inflammation, chemotaxis and exudation in ECs.MethodsELISA, qRT-PCR, immunofluorescence, flow cytometry and transwell assays were used to investigate the effects of APOC3 on human umbilical vein endothelial cells (HUVECs). SiRNA-induced TNF-α and JAM-1 silencing were used to observe how APOC3 influenced the inflammatory process in the ECs.ResultsOur results showed that APOC3 was closely associated with the inflammatory process in ECs, and that this process was characterized by the increased expression of TNF-α. Inflammatory processes further disrupted the tight junctions (TJs) between HUVECs by causing increased expression of JAM-1. JAM-1 was involved in maintaining the integrity of TJs, and it promoted the assembly of platelets and the exudation of leukocytes. Changes in its expression promoted chemotaxis and the exudation of ECs, which contributed to atherosclerosis. While the integrity of the TJs was disrupted, the adhesion of THP-1 cells to HUVECs was also increased by APOC3.ConclusionsIn this study, we describe the mechanism by which APOC3 causes inflammation, chemotaxis and the exudation of ECs, and we suggest that controlling the inflammatory reactions that are caused by APOC3 may be a new method to treat CVD.

Thymoquinone reduces cardiac damage caused by hypercholesterolemia in apolipoprotein E-deficient mice

“…This process is mediated by several independent pathways, including SR-A, class B (CD36), and LOX-1 [ 23 – 25 ] . Pro-inflammatory genes (TNF-α and IL-6) were reported to be expressed at high levels and to contribute to cardiovascular diseases caused by hyperlipidemia [ 26 , 27 ] .…”

Biological Consequences of Dysfunctional HDL

“…Furthermore, the ACCENTUATE study with evacetrapib [134] showed that, although the treatment increased cholesterol efflux capacity, it also generated HDL particles with increased apoC-III content. ApoC-III-enriched HDL are less functional [135,136] and might perhaps provide apoC-III to the arterial wall, which may trigger an inflammatory process in endothelial cells, characterized by increased expression of pro-inflammatory cytokines and increased adhesion of monocytes, as well as alterations of endothelial apoptosis [135,[137][138][139]. These findings suggest that, although effective in improving the overall lipid profile, pharmacological CETP inhibition might not associate to a vascular protective effect.…”

Hypertriglyceridemia and atherosclerosis

“…Studies have also suggested that TNF-α concentrations are positively associated with VLDL-C concentrations [ 84 ], which also can be found in the PTH rabbits [ 59 ]. A recent study has showed TNF-α overexpression increased expression of JAM-1, which promoted the chemotaxis and exudation of cells to cause atherosclerosis [ 85 ].…”