Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism.

The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.

The Anti-atherosclerotic Effects of Natural Polysaccharides: From Phenomena to the Main Mechanisms of Action.

Polysaccharides (PSs) of plant origin have a variety of biological activities, including antiatherosclerotic, but their use in atherosclerosis therapy is hindered by insufficient knowledge based on the cellular and molecular mechanisms of action. In this review, the influence of several natural PSs on the function of macrophages, viral activity and macrophage cholesterol metabolism has been discussed, considering the tight interplay between these aspects in the pathogenesis of atherosclerosis. The anti-atherosclerotic activities of natural PSs related to other mechanisms have also been explored. Directions for further research of the antiatherosclerotic effects of natural PSs have been outlined, the most promising of which can be nutrigenomic studies.

Polyphenols can Potentially Prevent Atherosclerosis and Cardiovascular Disease by Modulating Macrophage Cholesterol Metabolism.

Arterial atherosclerosis is the main pathological cause of coronary artery disease and peripheral arterial disease. Atherosclerosis is a chronic condition characterized by the presence of cholesterol-rich macrophages in the arterial intima. Accumulation of cholesterol in these macrophages is due to increased oxidation of low-density lipoprotein (LDL) and its uptake via scavenger receptors on the macrophages. Cholesterol efflux from the cholesterol-laden macrophages into high-density lipoprotein (HDL) is also a key process in maintaining cholesterol homeostasis and preventing cholesterol accumulation. Four pathways for the efflux of cholesterol to HDL exist in macrophages, including passive and active pathways. Several HDL characteristics determine cholesterol efflux capacity, namely composition, oxidative status, and HDL size. Oxidation of LDL and HDL, as well as an imbalance in cholesterol uptake and efflux, could lead to the accumulation of cholesterol in macrophages and initiation of atherosclerogenesis. Epidemiological studies have demonstrated that polyphenol-rich foods reduce cardiovascular events in the general population and in patients at risk of cardiovascular diseases. Many studies have reported that polyphenols in polyphenol-rich foods have anti-atherosclerotic properties by preventing cholesterol accumulation in macrophages through the suppression of lipoproteins oxidation and regulation of cholesterol uptake and efflux.