Background Oxidative modification of LDL plays an important role in vascular injury. Most studies have focused on harsh oxidation products, but not oxidized phospholipids. The purpose of this project was to test 1) if oxidized phospholipids disrupt endothelial function and 2) if vascular endothelial growth factor (VEGF-A) counteracts this effect. Oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) is an oxidized phospholipid mixture in minimally oxidized LDL and was tested. To demonstrate possible in vivo significance, human sera with either low or high lipid hydroperoxide levels were also tested.
Methods and Results 1) Human microvascular endothelial cells (HMEC) were incubated with 50 μg/ml Ox-PAPC, 200 μg/ml LDL, or media containing 20% human serum. In wounding/migration assays, [3H]thymidine incorporation assays and immunoblotting for phospho-Akt, Ox-PAPC inhibited migration by 97%, proliferation by 88%, and decreased Akt phosphorylation 2.5 fold. PAPC and LDL had no significant effect. High lipid hydroperoxide serum reduced endothelial migration by 63%, reduced proliferation by 53%, and reduced Akt phosphorylation 2 fold compared to low lipid hydroperoxide serum. 2) Bovine aortic endothelial cells (BAEC) were treated with Ox-PAPC, 100 μg/ml VEGF, and Ox-PAPC+VEGF. VEGF stimulated cell proliferation by 62.3% and increased Akt phosphorylation 1.5 fold over controls. Ox-PAPC+VEGF restored results to control levels.
Conclusion and Significance 1) Oxidized phospholipids and elevated lipid hydroperoxide sera can impair endothelial function. This may, in part, explain the increased atherosclerosis in patients with elevated lipid oxidation products in vivo. 2) VEGF overcomes Ox-PAPC's inhibitory effect. Further investigation of Ox-PAPC's mechanism of action and VEGF's counteraction may provide insight into atherosclerosis
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