Platelet secretory products enhance LDL receptor activity and inhibit scavenger receptor activity in human monocyte derived macrophages.
Macrophage cholesterol accumulation is an early event in atherogenesis. Platelet secretory products have the potential to affect macrophage cholesterol accumulation through their effect on cellular lipoprotein uptake via the low density lipoprotein (LDL) or the scavenger receptor pathways. Preincubation of human monocyte-derived macrophages (HMDM) for 16 hours at 37 degrees C with serotonin, ADP, fibrinogen, fibronectin and platelet-derived growth factor (PDGF), followed by washout of these substances, significantly enhanced LDL uptake by 25% to 75%, whereas acetyl LDL (AcLDL) degradation (AcLDL is taken up by the scavenger receptor), was substantially reduced by 40% to 60% (except for ADP). The effect of serotonin (0 to 75 mumol/L) on macrophage interaction with lipoproteins was further analyzed and revealed a dose-dependent effect on both stimulation of macrophage LDL degradation and cholesterol esterification by up to 2.5 times, as well as an inhibition of the cellular uptake of AcLDL by up to 1.5 times. Analysis of the regulatory effect of serotonin on macrophage lipoprotein uptake revealed that the main effect of serotonin on the uptake of both lipoproteins was to change the affinity of the lipoproteins toward their specific receptor without a significant effect on the number of binding sites. The next questions addressed are whether substances that are known to be secreted by activated platelets can also modify LDL, and whether this modification can alter the interaction between LDL and macrophages. LDL treated with all of the studied substances demonstrated significantly enhanced cellular degradation compared with untreated LDL. The data thus demonstrate that substances such as those released from activated platelets can selectively affect macrophage LDL and scavenger receptor activities.(ABSTRACT TRUNCATED AT 250 WORDS)
Aviram
M
M
Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel.
D001792:Blood Platelets / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins; D009000:Monocytes / Q000166:cytology*; D011971:Receptors, Immunologic / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012701:Serotonin / Q000494:pharmacology
D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D012701:Serotonin