The Peroxisome Proliferator-Activated Receptor delta Agonist, GW501516, Inhibits Angiogenesis through Dephosphorylation of Endothelial Nitric Oxide Synthase.
- Author:
Jae Bok KIM
1
;
Seok Hong LEE
;
Jihyun AHN
;
Jaetaek KIM
Author Information
- Publication Type:Original Article
- Keywords: Aortic endothelial cells; GW501516; Nitric oxide; Angiogenesis
- MeSH: Adipose Tissue; Animals; Antibodies, Phospho-Specific; Apoptosis; Atherosclerosis; Brain; Chickens; Chorioallantoic Membrane; DEET; Endothelial Cells; Humans; Ligands; Mice; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroso Compounds; Peroxisomes; Phosphorylation; PPAR delta; Thiazoles; Tissue Donors
- From:Journal of Lipid and Atherosclerosis 2012;1(1):11-20
- CountryRepublic of Korea
- Language:English
- Abstract: OBJECTIVE: Peroxisome proliferator-activated receptor delta (PPAR-delta) is an ubiquitously expressed nuclear receptor that has been implicated in adipose tissue formation, brain development, and atherosclerosis. Despite mouse studies demonstrating that PPAR-delta activation has favorable anti-atherogenic properties by improving systemic lipid profiles, the relationship between PPAR-delta agonist and angiogenesis is unknown. We hypothesized that PPAR-delta ligands modulate the angiogenesis. METHODS: To test this hypothesis we treated primary cultures of bovine aortic endothelial cells with PPAR-delta specific ligand, GW501516 (50-800 nM) for 6 h. RESULTS: GW501516 dose-dependently decreased nitric oxide production without alteration in endothelial nitric oxide synthase (eNOS) expression. Analysis with phospho-specific antibodies against eNOS demonstrated that GW501516 significantly decreased the phosphorylation of eNOS at Serine1179 (eNOS-Ser1179). Concurrently, GW501516 also decreased the Akt phosphorylation. GW501516 did not affect endothelial cell proliferation or induce apoptosis. However, GW501516 inhibited endothelial cell migration, and tube formation in a high nanomolar concentration. The inhibition of endothelial cell tube formation by GW501516 was prevented by addition of the nitric oxide donor, DETA NONOate (5 microM). GW501516 was also found to inhibit angiogenesis in vivo in the chicken chorioallantoic membrane assay. CONCLUSION: These results provide that high nanomolar range of GW501516 inhibits angiogenesis by a mechanism involving dephosphorylation of eNOS-Ser1179.
