Abstract
It has recently been shown that macrophage proliferation occurs during the progression of atherosclerotic lesions and that oxidized low density lipoprotein (LDL) stimulates macrophage growth. Possible mechanisms for this include the interaction of oxidized LDL with integral plasma membrane proteins coupled to signaling pathways, the release of growth factors and autocrine activation of growth factor receptors, or the potentiation of mitogenic signal transduction by a component of oxidized LDL after internalization. The present study was undertaken to further elucidate the mechanisms involved in the growth-stimulating effect of oxidized LDL in macrophages. Only extensively oxidized LDL caused significant growth stimulation, whereas mildly oxidized LDL, native LDL, and acetyl LDL were ineffective. LDL that had been methylated before oxidation (to block lysine derivatization by oxidation products and thereby prevent the formation of a scavenger receptor ligand) did not promote growth, even though extensive lipid peroxidation had occurred. The growth stimulation could not be attributed to lysophosphatidylcholine (lyso-PC) because incubation of oxidized LDL with fatty acid-free bovine serum albumin resulted in a 97% decrease in lyso-PC content but only a 20% decrease in mitogenic activity. Similarly, treatment of acetyl LDL with phospholipase A2 converted more than 90% of the initial content of phosphatidylcholine (PC) to lyso-PC, but the phospholipase A2-treated acetyl LDL was nearly 10-fold less potent than oxidized LDL at stimulating growth. Platelet-activating factor receptor antagonists partly inhibited growth stimulation by oxidized LDL, but platelet-activating factor itself did not induce growth. Digestion of oxidized LDL with phospholipase A2 resulted in the hydrolysis of PC and oxidized PC but did not attenuate growth induction. Native LDL, treated with autoxidized arachidonic acid under conditions that caused extensive modification of lysine residues by lipid peroxidation products but did not result in oxidation of LDL lipids, was equal to oxidized LDL in potency at stimulating macrophage growth. Albumin modified by arachidonic acid peroxidation products also stimulated growth, demonstrating that LDL lipids are not essential for this effect. These findings suggest that oxidatively modified apolipoprotein B is the main growth-stimulating component of oxidized LDL, but that oxidized phospholipids may play a secondary role.
Highlights
That oxidatively modified apolipoprotein B is the main growth-stimulating component of oxidized low density lipoprotein (LDL), but that oxidized phospholipids may play a secondary role
The mitogenic effect of oxidized LDL was mediated by protein kinase C [15] and was attributed to lysophosphatidylcholine that is generated during LDL oxidation through enzymatic hydrolysis of PC by platelet-activating factor (PAF) acetylhydrolase, an enzyme that is normally associated with LDL [16, 17]
These interpretations conflict with ours, the actual data are in general agreement. We confirmed their findings that PLA2treated acetyl LDL can mimic the effect of oxidized LDL and that macrophages lacking scavenger receptors are less responsive to oxidized LDL than control cells
Summary
That oxidatively modified apolipoprotein B is the main growth-stimulating component of oxidized LDL, but that oxidized phospholipids may play a secondary role. Oxidized LDL exhibits many other potentially atherogenic actions in vitro [2], including direct chemoattractant activity for circulating monocytes [4], induction of monocyte chemotactic protein-1 expression [5], and enhancement of the expression of endothelial adhesion molecules VCAM-1 (vascular cell adhesion molecule-1), ICAM-1 (intercellular adhesion molecule 1), and P-selectin (6 –9) These effects would tend to increase the number of macrophages within the arterial intima at sites where oxidized LDL was present. Modified ApoB Induces Growth of Macrophages and rat vascular smooth muscle cells [19] In these cells, the mitogenic effect of oxidized LDL was attributed to an oxidized phospholipid with PAF-like bioactivity and was blocked with. The present studies were done to clarify the mechanism by which oxidized LDL stimulates macrophage growth
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