Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets

ABSTRACT

Introduction

Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide.

Areas Covered

Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development.

Exert Opinion

As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.

KEYWORDS:

• Foam cells
• atherosclerosis
• cholesterol
• lipoproteins
• therapeutics
• autophagy
• efferocytosis
• plaque
• atheroma

Article highlights

• Current approaches to mitigating atherosclerosis are largely preventative in nature or aimed at addressing early-stage aspects of the disease with systemic therapeutics, such as lipid-lowering agents, antidiabetic drugs, and anti-inflammatory medications.

• Foam cells are ideal targets to affect the resolution of existing atherosclerotic lesions, because they are integral to plaque development and a highly malleable cell type.

• Cutting edge therapeutics include biomimetics, antagomirs, and combinatorial approaches for mitigating different aspects of pathophysiology, such as inflammation, cholesterol flux, and efferocytosis of lipid-laden foam cells.

• Major hurdles to generating new and improved therapies to target lipid-laden foam cells include differences in pathophysiology between humans and small animal models, as well as the heterogeneity and complexity of foam cell subsets.

• Future therapeutic development endeavors will include nano-medicinal, multi-targeted approaches that leverage new technologies and discoveries, such as the role of noncoding RNA and exosomes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Search strategy

PubMed was searched using the following terms in various combinations: atherosclerosis, plaque, thrombosis, cardiovascular disease, immunometabolism, foam cells, lipid-laden foam cells, macrophages, vascular smooth muscle cells, endothelial cells, therapeutics, mTOR, cholesterol flux, LDL, HDL, VLDL, dyslipidemia, apoptosis, efferocytosis, autophagy, lipophagy, LDL aggregates, apoptosis, cell death, senescence, bile sequestrants, cholesterol metabolism, lipid droplet factors, PPAR agonists, fibrates, statins, exosomes, noncoding RNAs, macrophage scavenger receptors, cholesterol esterification, LXR agonists, microbiome, exosomal digestion, cholesterol crystals, mitophagy, aggrephagy, necroptosis, autosis, parthanatos, PARP inhibitors, animal models of atherosclerosis, and the majority of individual drugs and molecules mentioned.

Additional information

Funding

This work was supported by grants from the NIH and US Department of Veterans Affairs.