New Strategies to Promote Macrophage Cholesterol Efflux.

Jacques Genest,Hong Y. Choi,Shiwon Choi,Isabelle Ruel

doi:10.3389/fcvm.2021.795868

Jacques Genest, Hong Y. Choi + Show 2 more

Open Access

https://doi.org/10.3389/fcvm.2021.795868

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Abstract

The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.

Highlights

Atherosclerosis is a major cause of cardiovascular disease in humans and atherosclerotic cardiovascular diseases (ASCVD) including heart attack, stroke and peripheral artery disease represent the leading cause of morbidity and mortality worldwide [1]
Monocyte-derived macrophages are the primary component of atherosclerotic plaques and phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells have been most widely used to model human monocytederived macrophages
PMA has been effectively used to differentiate THP-1 monocytes into macrophages, the differentiation procedure is highly variable across studies, resulting in generating THP-1 cells in varying degrees of differentiation

Summary

INTRODUCTION

Atherosclerosis is a major cause of cardiovascular disease in humans and atherosclerotic cardiovascular diseases (ASCVD) including heart attack, stroke and peripheral artery disease represent the leading cause of morbidity and mortality worldwide [1]. We observed that 1 nM docetaxel was sufficient to significantly promote the cholesterol efflux in the 37-day cultured CD14highDSC1low THP-1 cells These results indicate that the DSC1 expression level is a factor determining effective docetaxel doses and that docetaxel may become a potent promoter of ABCA1-mediated cholesterol efflux in differentiated macrophages. The identification of docetaxel as a potent blocker of apoA-I-DSC1 interactions is exciting in several aspects of drug development: (a) the localization of the DSC1 extracellular domain at the cell surface makes it an easy target to access, (b) reduced expression of DSC1 in differentiated macrophages improves pharmacological efficacy of docetaxel in blocking DSC1, and (c) the high potency of docetaxel allows to use low therapeutic doses and to reduce adverse side effects Combined, these data advise us to develop docetaxel and docetaxel-derived compounds as new drugs for the promotion of ABCA1-mediated cholesterol efflux

SUMMARY

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