Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPARgamma ligands stimulate endothelial-derived nitric oxide release (*NO) to protect the vascular wall.


RESULTS
The PPARgamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPARgamma was transcriptionally functional. Treatment with 15d-PGJ2 or ciglitazone significantly increased release of *NO from PAECs or human aortic endothelial cells and augmented calcium ionophore-induced *NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in *NO release caused by treatment with 15d-PGJ2 occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor alpha-amanitin. Overexpression of PPARgamma or treatment with 9-cis retinoic acid also enhanced PAEC *NO release. Neither 15d-PGJ2 nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ2, but not ciglitazone, decreased eNOS protein.


CONCLUSIONS
Taken together, these findings demonstrate that PPARgamma ligands stimulate *NO release from endothelial cells derived from multiple vascular sites, through a transcriptional mechanism unrelated to eNOS expression.
Calnek
David S
DS
Department of Medicine, Veterans Affairs and Emory University, Medical Centers, Decatur, Ga 30033, USA. dcalnek@hotmail.com
Mazzella
Louis
L
Roser
Susanne
S
Roman
Jesse
J
Hart
C Michael
CM
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008024:Ligands; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000502:physiology*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology / Q000201:enzymology / Q000502:physiology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D015230:Prostaglandin D2; C039671:ciglitazone