Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs

Abstract

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

Keywords: atherosclerosis; foam cell formation; lipid metabolism; noncoding RNAs.

Figure 1

The mechanisms and molecules involved in cholesterol metabolism and homeostasis and the regulatory effects of Non-encoding RNAs are depicted in a foam cell. Cholesterol metabolism involves cholesterol influx, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol homeostasis in the macrophage. Scavenger receptors SRA-1, CD36 and LOX1 are involved in oxLDL uptake. The gene expression of these receptors is downregulated in part A (see above); that is, non-encoding RNAs that have anti-atherosclerotic properties and are upregulated by part B ncRNAs, which are atherogenic and lead to lipid accumulation in macrophages. Cholesterol efflux is a pathway that transports excess free cholesterol from the cell, mainly via ABCA1, ABCG1, as well as SR-B1 transporters, leading to the formation of HDL and apoa1. The ncRNAs that reduce the formation of foam cells by increasing cholesterol efflux are specified in part C, as well as ncRNAs that lead to induction of the formation of foam cells by reducing cholesterol efflux, which are specified in part D. In cholesterol esterification, ACAT-1 and neutral cholesterol ester hydrolase (NCEH) play a key role in catalyzing the esterification of cholesterol and removing free cholesterol from foam cells, respectively. ACAT1 re-esterifies excess FC to promote the biosynthesis of CE that is stored in lipid droplets. In part E, microRNAs have been listed that reduce cholesterol esterification and increase the accumulation of free cholesterol, which ultimately promotes foam cell formation. Reducing foam cell apoptosis can stabilize atherosclerotic plaque and prevent the progression and worsening of atherosclerosis. ncRNAs that reduce foam cell apoptosis are shown in part F. = decrease, = increase.

Figure 2

Direct and indirect effects of different Non-coding RNAs on the expression of ABCA1, which has a large 3′UTR region and is one of the most important transporters in cholesterol efflux [144,145]. In direct mechanism: non-coding RNAs able to bind to 3′UTR of ABCA1 mRNA transcript which ABCA1 expression regulate, in indirect mechanism: non-coding RNAs were not able to bind to 3′UTR of ABCA1 mRNA transcript although these noncoding RNAs that bind to 3′UTR of other mRNA transcript in turn regulate ABCA1 expression. It has also been shown that reducing inflammation increases the expression of this transporter and has a negative role in the formation of foam cells by increasing cholesterol efflux [148,149].