Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives

Abstract

E ndothelial nitric oxide synthase (eNOS) is one of three NOS isoforms that catalyze the formation of nitric oxide (NO) and L-citrulline by the oxidation of the guanido-nitrogen group of L-arginine. The cardiovascular importance of this reaction relies on the formation of NO, a signaling molecule that regulates vascular tone, platelet aggregation, oxidative stress, leukocyte adherence, and smooth muscle cell mitogenesis. 1 Peroxisome proliferator-activated receptors (PPARs) are a subfamily of the nuclear receptor family of transcription factors that control the expression of key genes involved in the regulation of metabolism, inflammation, and thrombosis. 2 Transcriptional control involves ligand activation followed by either heterodimerization with a retinoid X receptor and binding to the promoter region of target genes, or a DNA-binding independent mechanism that interferes negatively with proinflammatory factor pathways. Of the three PPAR isoforms (␣, ␤/␦, and ␥), PPAR-␣ is expressed chiefly in fatty acid-oxidizing tissues including liver, skeletal muscle, and heart, but also in endothelial and vascular smooth muscle cells and macrophages within the arterial wall. Despite a plethora of basic research demonstrating that PPAR-␣ activation by synthetic ligands (eg, fibrates) has favorable antiatherogenic properties, 2 the corresponding effects on eNOS and the biology of NO has surprisingly not yet been explored. See page 658In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Goya et al 3 demonstrate for the first time that specific PPAR-␣ agonists, such as fenofibrate, regulate eNOS in cultured endothelial cells. Using classical molecular biology techniques and bovine aortic endothelial cells as a model, fenofibrate was shown to increase the mRNA expression, protein level, and enzyme activity of eNOS in a dosedependent manner at concentrations within the range of its EC 50 value for human PPAR␣. The authors found that the eNOS promoter sequence does not possess a PPAR response element and, accordingly, showed that fenofibrate did not enhance eNOS promoter activity. However, in mRNA stability assays, fenofibrate increased the half-life of eNOS mRNA. The observation that PPAR-␣ agonists stabilize mRNA levels is unusual and raises the question of whether these effects occur via PPAR-␣. Further studies employing in vitro gene knock-down technology and/or in vivo analysis on PPAR-␣-deficient mice are required to answer this important issue and to demonstrate the pathophysiological relevance of these findings. Goya et al 3 also present limited data indicating that the effect of fenofibrate on eNOS was shared by bezafibrate, a less specific PPAR-␣ agonist, but not rosiglitazone, a highly specific PPAR-␥ agonist.From a molecular perspective, these findings have to be placed within the context of the other antiatherogenic mechanisms of action of PPAR-␣ agonists 2 and the complexity of the regulation of eNOS. 4 PPAR-␣ is classically involved in the systemic regulation of lipid and lipoprotein metabolism b...

Endothelial Progenitor Cells and Vascular Biology in Diabetes Mellitus: Current Knowledge and Future Perspectives

“…All these effects were prevented by supplementation of the culture medium with rosiglitazone, which hampered CRP-induced NO reduction in EPCs [143].…”

PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats

“…PPARa is expressed in endothelial cells and it has been demonstrated that PPARa activation is involved in several endothelial functions as leukocyte recruitment, inflammatory signalling, and vascular functions [13]. The beneficial effects of fenofibrate on vascular function may be partly due to improved endothelial NO availability, as it has been demonstrated that PPARa activation increases NO production in endothelial cells [14][15][16]. Besides, PPARa activation has also been shown to decrease the expression of COX-1 and the release of thromboxane A 2 (TXA 2 ) [17].…”

Kmup-1 Protects Kidney from Streptozotocin-Induced Pro-Inflammation in Early Diabetic Nephropathy by Restoring Enos/Pparγ and Inhibiting MMP-9

“…Moreover, eNOS/ PPARy is involved in inhibiting ON (18). KMUP-l has been indicated with anti-inflammatory property, potentially up-regulating PPARy-eNOS expression in renal tissue of ON (19)(20).…”