HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services 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 Ye, Y. Articles by Birnbaum, Y. Search for Related Content PubMed PubMed Citation Articles by Ye, Y. Articles by Birnbaum, Y.

Phosphorylation of 5-Lipoxygenase at Ser⁵²³ by Protein Kinase A Determines Whether Pioglitazone and Atorvastatin Induce Proinflammatory Leukotriene B₄ or Anti-Inflammatory 15-Epi-Lipoxin A₄ Production

Yumei Ye^*,, Yu Lin^*, Jose R. Perez-Polo, Barry F. Uretsky^*, Zaiming Ye, Brian C. Tieu and Yochai Birnbaum^1,*,

^* Division of Cardiology, Department of Biochemistry and Molecular Genetics, and Graduate School of Biomedical Science, University of Texas Medical Branch, Galveston, TX 77555

The 5-lipoxygenase (5LO) produces leukotriene B₄ and 15-epilipoxin-A₄ (15-epi-LXA₄). Phosphorylation at Ser⁵²³ by protein kinase A (PKA) prevents 5LO shift to the perinuclear membrane. Atorvastatin and pioglitazone up-regulate 15-epi-LXA₄ production in the heart. We assessed whether phosphorylation of 5LO by PKA determines whether 5LO interacts with the membranous cytosolic phospholipase A₂ (cPLA₂) to produce leukotriene B₄ or with cyclooxygenase-2 (COX2) to produce 15-epi-LXA₄. Rats received either pioglitazone, atorvastatin, pioglitazone plus atorvastatin, vehicle, or LPS. Rat myocardial cells were incubated with pioglitazone plus atorvastatin, pioglitazone plus atorvastatin plus H-89 (PKA inhibitor), H-89, or vehicle for 8 h. Pioglitazone and atorvastatin did not affect total 5LO expression. However, both increased 5LO levels in the cytosolic fraction. H-89 caused a shift of 5LO to the membranous fraction in atorvastatin- and pioglitazone-treated rats. Pioglitazone and atorvastatin increased phospho-5LO levels. H-89 attenuated this increase. Both pioglitazone and atorvastatin increased COX2 levels in the cytosolic fraction and the membranous fraction. H-89 prevented this increase. Pioglitazone and atorvastatin increased cPLA₂ expression in the membranous fraction. This effect was not attenuated by H-89. Pioglitazone plus atorvastatin increased 15-epi-LXA₄ levels. H-89 attenuated the effect of pioglitazone plus atorvastatin. Pioglitazone plus atorvastatin plus H-89 increased leukotriene B₄ levels. Coimmunoprecipitation showed that without H-89, atorvastatin and pioglitazone induced an interaction between 5LO and COX2 in the cytosolic fraction, whereas when H-89 was added, 5LO interacted with cPLA₂ on the membranous fraction. The 5LO phosphorylation determines whether 15-epi-LXA₄ (anti-inflammatory) or leukotriene B₄ (inflammatory mediator) is produced.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Yochai Birnbaum, Division of Cardiology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Boulevard, Galveston, TX 77555-0553. E-mail address: yobirnba{at}utmb.edu

² Abbreviations used in this paper: PIO, pioglitazone; 5LO, 5-lipoxygenase; 15-epi-LXA₄, 15-epi-lipoxin A₄; 15R-HETE, (15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid; AA, arachidonic acid; ATV, atorvastatin; COX2, cyclooxygenase-2; cPLA₂, cytosolic phospholipase A₂; Ct, threshold cycle; DAPI, 4',6'-diamidino-2-phenylindole; LT, leukotriene; P-5LO, phosphorylated 5LO; PKA, protein kinase A.

This article has been cited by other articles:

				Y. Alvarez, C. Municio, S. Alonso, J. A. S. Roman, M. S. Crespo, and N. Fernandez Cyclooxygenase-2 Induced by Zymosan in Human Monocyte-Derived Dendritic Cells Shows High Stability, and Its Expression Is Enhanced by Atorvastatin J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 987 - 994. [Abstract] [Full Text] [PDF]