Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Even though very low or high levels of cholesterol can compromise cellular functions, cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid-mediated inflammatory responses. We have previously shown that the parent omega-6 fatty acid linoleic acid can markedly activate vascular endothelial cells. We now propose that membrane cholesterol can modify and inhibit linoleic acid-mediated endothelial cell dysfunction. To test this hypothesis, pulmonary artery endothelial cells were incubated with cholesterol (0 to 100 μmol/L) for 24 hours and then treated with 90 μmol/L of linoleic acid (18:2n-6) for 6 to 24 hours. In control cells, treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor-κB (NF-κB) leading to the upregulation of interleukin-6 (IL-6). In addition, the expression of endothelial nitric oxide synthase (eNOS) was altered, with linoleic acid increasing eNOS activity. In contrast, enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid-induced activation of NF-κBand the production of IL-6. Prior exposure to 50 μmol/L cholesterol also prevented the fatty acid-induced increase in eNOS activation. Cholesterol loading activated peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor that can decrease inflammatory responses. Furthermore, the PPAR-γ agonist thiazolidinedione markedly downregulated the NF-κB activation mediated by linoleic acid. Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels.
|Number of pages||8|
|Journal||Metabolism: Clinical and Experimental|
|State||Published - Apr 1 2003|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism