Macrophages bind LDL using heparan sulfate and the perlecan protein core

Abstract

The retention of low-density lipoprotein (LDL) is a key process in the pathogenesis of atherosclerosis and largely mediated via smooth-muscle cell-derived extracellular proteoglycans including the glycosaminoglycan chains. Macrophages can also internalize lipids via complexes with proteoglycans. However, the role of polarized macrophage-derived proteoglycans in binding LDL is unknown and important to advance our understanding of the pathogenesis of atherosclerosis. We therefore examined the identity of proteoglycans, including the pendent glycosaminoglycans, produced by polarized macrophages to gain insight into the molecular basis for LDL binding. Using the quartz crystal microbalance with dissipation monitoring technique, we established that classically activated macrophage (M1)- and alternatively activated macrophage (M2)-derived proteoglycans bind LDL via both the protein core and heparan sulfate (HS) in vitro . Among the proteoglycans secreted by macrophages, we found perlecan was the major protein core that bound LDL. In addition, we identified perlecan in the necrotic core as well as the fibrous cap of advanced human atherosclerotic lesions in the same regions as HS and colocalized with M2 macrophages, suggesting a functional role in lipid retention in vivo . These findings suggest that macrophages may contribute to LDL retention in the plaque by the production of proteoglycans; however, their contribution likely depends on both their phenotype within the plaque and the presence of enzymes, such as heparanase, that alter the secreted protein structure.

Catalpol Inhibits Macrophage Polarization and Prevents Postmenopausal Atherosclerosis Through Regulating Estrogen Receptor Alpha

“…M2 macrophages are far away from the lipid core of plaque, and primarily distributed in the stable area of the plaque. M2 macrophages possess a solid ability to remove lipids by phagocytosis (Ng et al, 2021). They can secrete anti-inflammatory cytokines (such as IL-10, TGF-β) to help wound healing, which plays a significant role in tissue repair.…”

Smooth Muscle Cell—Macrophage Interactions Leading to Foam Cell Formation in Atherosclerosis: Location, Location, Location

“…Though SMCs are the major source of proteoglycan secretion in the intima, macrophages can also secrete proteoglycans that contribute to lipoprotein retention ( Kolset and Gallagher, 1990 ; Wight, 2018 ; Ng et al, 2021 ). For example, macrophages synthesize chondroitin sulfate proteoglycans, which connect atherogenic LDL and SRA in proximity, promoting more lipoprotein uptake and foam cell development ( Christner, 1988 ; Santiago-García et al, 2003 ).…”

“…Analysis of macrophage conditioned medium showed that macrophage colony-stimulating factor (MCSF) could complex with proteoglycans when secreted by macrophages, which promoted monocyte differentiation and lipoprotein retention at the same time, contributing to foam cell development ( Chang et al, 1998 ) . Recently, Ng and colleagues also identified that perlecan was the major proteoglycan secreted by human macrophages involved in LDL retention, though perlecan was also suggested to be low in human lesions ( Tran et al, 2007 ; Ng et al, 2021 ). It was observed that proteoglycan synthesis by macrophages was upregulated when macrophages received inflammatory stimuli or were under hypoxia stress.…”

Extracellular matrix: paving the way to the newest trends in atherosclerosis

“…The retention ability of proteoglycans is mainly addressed in the context of SMCs and endothelial cells. However, macrophage-derived proteoglycans notably also bind lipoproteins via both their protein core and heparan sulphate GAG chains [ 7 ▪▪ ]. In the same study, the authors reported that the matrisome of macrophages is sensitive to macrophage polarization.…”

“…In support of these observations, it was reported that HS biosynthesis is fine-tuned during macrophage polarisation, depicting their resolving or proinflammatory macrophage phenotype during atherosclerosis-related inflammation [ 21 ]. Recently, it was reported that M1 macrophages produced PGs with a higher level of HS chain sulphation compared with M2 macrophages [ 7 ▪▪ ]. These observations encourage further studies on the significance of HS in the immune signature of the plaques that may lead to future improved treatment against plaque destabilization.…”