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The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by
L T Malden1, A Chait, E W Raines
1Department of Pathology, University of Washington, Seattle 98195.
Abstract:
Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.
Insights
Oxidized low-density lipoproteins (LDL) reduce platelet-derived growth factor (PDGF) expression in macrophages. This finding is crucial for understanding atherogenesis and potential therapeutic targets in cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Atherosclerosis Research
- Cellular and Molecular Medicine
Background:
- Macrophages are key players in atherogenesis, accumulating lipids and expressing platelet-derived growth factor (PDGF).
- Modified lipoproteins, particularly oxidized low-density lipoproteins (LDL), are implicated in atherosclerotic lesion development.
- PDGF secreted by macrophages influences smooth muscle cell behavior in the artery wall.
Purpose of the Study:
- To investigate how different forms of modified low-density lipoproteins (LDL) affect PDGF gene expression, synthesis, and secretion in human monocyte-derived macrophages.
- To determine the impact of oxidized LDL on both basal and stimulated PDGF production.
Main Methods:
- Human blood monocyte-derived macrophages were cultured and exposed to various modified LDL preparations.
- Analysis of PDGF-B messenger RNA (mRNA) expression and protein secretion was performed.
- Lipid accumulation and foam cell formation were assessed.
Main Results:
- Cell-free oxidized LDL inhibited constitutive PDGF-B mRNA expression and PDGF secretion in a dose-dependent manner.
- Oxidized LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression.
- These inhibitory effects were independent of lipid uptake and loading, appearing within 2 hours of exposure.
- The extent of LDL oxidation correlated with the degree of PDGF-B expression inhibition.
- Acetylated LDL and LDL aggregates increased cholesterol accumulation but did not consistently alter PDGF expression.
Conclusions:
- Uptake of oxidized LDL products modulates PDGF expression and secretion by macrophages.
- This modulation of PDGF may influence smooth muscle cell chemotaxis and mitogenesis in the artery wall.
- Findings suggest a novel mechanism by which oxidized LDL contributes to atherogenesis.