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.

Inflammatory Cells in Atherosclerosis

“…Foam cells present in the lesion are mainly a product of M2 macrophage differentiation forming foam cell clusters in the early stages. Initially functioning as a mechanism to remove the cytotoxic and pro-inflammatory ox-LDL in the intima, the macrophages are unable to process the increased influx of ox-LDL and accumulation of cholesteryl ester [ 42 , 76 , 77 ]. Ox-LDL accumulation in the endothelial barrier is facilitated by protein kinase C activation, which increases the permeability of the endothelial layer.…”

Cholesterol in the Cell Membrane—An Emerging Player in Atherogenesis

“…This may indicate an atherogenic effect of SAFAs in addition to their well-known effect on hypercholesterolemia. In addition to the transcription factors, the non-coding RNAs represent yet another form of regulation of monocyte differentiation [ 57 ].…”

Macrophages and Foam Cells: Brief Overview of Their Role, Linkage, and Targeting Potential in Atherosclerosis

“…Another approach targeting foam cells is to slow the foam cell degradation, which can potentially have an atheroprotective effect [ 77 ]. Among such approaches are promoting efferocytosis of apoptotic macrophages by using LXR ligands or glucocorticoids, activating PPARγ pathways, knockdown of apoptosis inhibitor of macrophages, targeting apoptotic pathways, such as the genetic inhibition of BAX or Bcl-2 and other atherogenic proteins, targeting secondary necrosis pathways (e.g., the clearance of apoptotic cells).…”