Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 1; pp. 52 - 57
• Main Authors: Calnek, David S, Mazzella, Louis, Roser, Susanne, Roman, Jesse, Hart, C Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.01.2003; Hagerstown, MD Lippincott
• Subjects: Animals; Aorta - cytology; Aorta - enzymology; Aorta - physiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - enzymology; Endothelium, Vascular - physiology; Enzyme Induction - drug effects; Enzyme Induction - physiology; Humans; Immunologic Factors - pharmacology; Ligands; Medical sciences; Nitric Oxide - metabolism; Nitric Oxide Synthase - biosynthesis; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Pulmonary Artery - cytology; Pulmonary Artery - enzymology; Pulmonary Artery - physiology; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Cytoplasmic and Nuclear - physiology; Swine; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - biosynthesis; Transcription Factors - physiology; Umbilical Veins - cytology; Umbilical Veins - enzymology; Umbilical Veins - physiology; endothelium; Endothelial cell; thiazolidinedione; Pathogenesis; Cardiovascular disease; Pig; Vascular disease; Vertebrata; Mammalia; Animal; Nitric oxide; Atherosclerosis; Artiodactyla; nitric oxide synthase; peroxisome proliferator-activated receptor γ; Ungulata; Peroxisome proliferator activated receptor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000044461.01844.C9

OBJECTIVE—Peroxisome proliferator-activated receptor γ (PPARγ) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPARγ ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall. METHODS AND RESULTS—The PPARγ ligands, 15-deoxy-Δ-prostaglandin J2 (15d-PGJ2) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPARγ 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 α-amanitin. Overexpression of PPARγ 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 PPARγ ligands stimulate ·NO release from endothelial cells derived from multiple vascular sites, through a transcriptional mechanism unrelated to eNOS expression.