'Blow my mind(in)' - mindin neutralization for the prevention of atherosclerosis?

Abstract

The hallmark features of atherosclerosis include accumulation of low-density lipoprotein (LDL) carrying cholesterol in the vessel wall, formation of lipid-laden foam cells, and the creation of a pro-inflammatory microenvironment. To date, no effective treatments are clinically available for increasing cholesterol efflux from vascular macrophages and inducing reverse cholesterol transport (RCT). In an article published recently in Clinical Science (vol 132, issue 6, 1199-1213), Zhang and colleagues identified the extracellular matrix protein mindin/spondin 2 as a positive regulator of atherosclerosis. Genetic knockout of mindin in apolipoprotein-E (apoE)-/- mice attenuated atherosclerosis, foam cell formation, and inflammation within the vessel wall. Conversely, selective overexpression of mindin in macrophages in apoE-/- mice was sufficient to promote the greater severity of atherosclerosis. Interestingly, foam cell formation was closely associated with the expression of cholesterol transporters (ABCA1 and ACBG1) that facilitate cholesterol efflux. Liver X receptor (LXR)-β is a key modulator of cholesterol transporter expression and formed direct interactions with mindin. Furthermore, the protective effects of mindin deficiency on foam cell formation were blocked by inhibition of LXR-β. This article highlights a novel role of mindin in modulating foam cell formation and atherosclerosis development in mice through direct regulation of LXR-β. Thus far, direct targetting of LXR-β via pharmacological agonists has proven to be problematic due to the lack of subtype selective inhibitors and associated adverse effects. Indirect targetting of LXR-β, therefore, via mindin inhibition offers a new therapeutic strategy for increasing LXR-β induced cholesterol efflux, reducing foam cell formation, and preventing or treating atherosclerosis.

• Authors: Neil MacRitchie, Pasquale Maffia
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 132 Issue 14 Pg. 1509-1512 (07 31 2018) ISSN: 1470-8736 [Electronic] England
• PMID: 30037838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Comment)
• Copyright: © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• ATP Binding Cassette Transporter 1
• Apolipoproteins E
• Extracellular Matrix Proteins
• Liver X Receptors
• mindin

Topics

• ATP Binding Cassette Transporter 1
• Animals
• Apolipoproteins E
• Atherosclerosis
• Extracellular Matrix Proteins
• Foam Cells
• Liver X Receptors
• Macrophages
• Mice