This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/4/506    most recent CIRCRESAHA.108.191114v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Di Francesco, L. Articles by Patrignani, P. Search for Related Content PubMed PubMed Citation Articles by Di Francesco, L. Articles by Patrignani, P. Related Collections Oxidant stress Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation Research. 2009;104:506.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Induction of Prostacyclin by Steady Laminar Shear Stress Suppresses Tumor Necrosis Factor- Biosynthesis via Heme Oxygenase-1 in Human Endothelial Cells

Luigia Di Francesco^*, Licia Totani^*, Melania Dovizio, Antonio Piccoli, Andrea Di Francesco, Tania Salvatore, Assunta Pandolfi, Virgilio Evangelista, Ryan A. Dercho, Francesca Seta, Paola Patrignani

From the Department of Medicine and Aging (L.D.F., M.D., A.D.F., T.S., P.P.), "G. d’Annunzio" University, Chieti, Italy; CeSI (L.D.F., M.D., A.D.F., T.S., A. Pandolfi, P.P.), Chieti, Italy; Mario Negri Sud (L.T., A. Piccoli, V.E.), Santa Maria Imbaro, Chieti, Italy; and Departments of Pharmacology and Toxicology (R.A.D.) and Physiology and Biochemistry (F.S.), Queen’s University, Kingston, Ontario, Canada.

Correspondence to Paola Patrignani, PhD, Sezione di Farmacologia, Dipartimento di Medicina e Scienze dell’Invecchiamento, Università "G. d’Annunzio", Via dei Vestini, 31, 66100 Chieti, Italy. E-mail ppatrignani{at}unich.it

Cyclooxygenase (COX)-2 is among the endothelial genes upregulated by uniform laminar shear stress (LSS), characteristically associated with atherosclerotic lesion-protected areas. We have addressed whether the induction of COX-2–dependent prostanoids in endothelial cells by LSS plays a role in restraining endothelial tumor necrosis factor (TNF)- generation, a proatherogenic cytokine, through the induction of heme oxygenase-1 (HO)-1, an antioxidant enzyme. In human umbilical vein endothelial cells (HUVECs) exposed to steady LSS of 10 dyn/cm² for 6 hours, COX-2 protein was significantly induced, whereas COX-1 and the downstream synthases were not significantly modulated. This was associated with significant (P<0.05) increase of 6-keto-prostaglandin (PG)F₁ (the hydrolysis product of prostacyclin), PGE₂, and PGD₂. In contrast, TNF- released in the medium in 6 hours (3633±882 pg) or detected in cells lysates (1091±270 pg) was significantly (P<0.05) reduced versus static condition (9100±2158 and 2208±300 pg, respectively). Coincident induction of HO-1 was detected. The finding that LSS-dependent reduction of TNF- generation and HO-1 induction were abrogated by the selective inhibitor of COX-2 NS-398, the nonselective COX inhibitor aspirin, or the specific prostacyclin receptor (IP) antagonist RO3244794 illuminates the central role played by LSS-induced COX-2–dependent prostacyclin in restraining endothelial inflammation. Carbacyclin, an agonist of IP, induced HO-1. Similarly to inhibition of prostacyclin biosynthesis or activity, the novel imidazole-based HO-1 inhibitor QC15 reversed TNF- reduction by LSS. These findings suggest that inhibition of COX-2–dependent prostacyclin might contribute to acceleration of atherogenesis in patients taking traditional nonsteroidal antiinflammatory drugs (NSAIDs) and NSAIDs selective for COX-2 through downregulation of HO-1, which halts TNF- generation in human endothelial cells.

Key Words: cyclooxygenase • endothelial cells • prostaglandins • prostanoids • shear stress • tumor necrosis factor-

This article has been cited by other articles:

				M. D. Salvado, A. Alfranca, A. Escolano, J. Z. Haeggstrom, and J. M. Redondo COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH2 for Transcellular Metabolism to PGE2 by Tumor Cells Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1131 - 1137. [Abstract] [Full Text] [PDF]