on September 15, 2005
Published online before print September 15, 2005, doi: 10.1161/01.ATV.0000186181.19909.a6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 11, 2005
Accepted on August 29, 2005
12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-
B
David T. Bolick ;
From the Cardiovascular Research Center (D.T.B., A.W., S.S., M.E.H., M.A.S., C.C.H.), and the Departments of Pharmacology (C.C.H.) and Microbiology (A.W.O., M.A.S.), University of Virginia, Charlottesville.
* To whom correspondence should be addressed. E-mail: cch6n{at}virginia.edu.
Background--12/15-lipoxygenase (12/15-LO) activity leads to the production of the proinflammatory eicosanoids 12-S-hydroxyeicosatetraenoic acid (12SHETE) and 13-S-hydroxyoctadecadienoic acid. We have previously shown a 3.5-fold increase in endothelial intercellular adhesion molecule (ICAM)-1 expression in mice overexpressing the 12/15-LO gene. We examined whether 12/15-LO activity regulated endothelial ICAM-1 expression.
Methods and Results--Freshly isolated aortic endothelial cells (EC) from 12/15-LO transgenic mice had significantly greater nuclear factor-
B (NF-B) activation and ICAM mRNA expression compared with C57BL/6J control. 12/15-LO transgenic EC showed elevated RhoA activity, and inhibition of RhoA using either C3 toxin or the Rho-kinase inhibitor Y-27632 blocked NF-B activation, ICAM-1 induction, and monocyte adhesion. Furthermore, we show that 12SHETE activates PKC
, which forms a complex with active RhoA and is required for NF-B-dependent ICAM expression in response to 12SHETE.
Conclusions--The 12/15-LO pathway stimulates ICAM-1 expression through the RhoA/PKC-dependent activation of NF-B. These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis.
This article has been cited by other articles:
 |
|
 |
|
  R. A. Gubitosi-Klug, R. Talahalli, Y. Du, J. L. Nadler, and T. S. Kern 5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy Diabetes, May 1, 2008; 57(5): 1387 - 1393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Harkewicz, K. Hartvigsen, F. Almazan, E. A. Dennis, J. L. Witztum, and Y. I. Miller Cholesteryl Ester Hydroperoxides Are Biologically Active Components of Minimally Oxidized Low Density Lipoprotein J. Biol. Chem., April 18, 2008; 283(16): 10241 - 10251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Tew, E. L. Lorimer, T. J. Berg, H. Zhi, R. Li, and C. L. Williams SmgGDS Regulates Cell Proliferation, Migration, and NF-{kappa}B Transcriptional Activity in Non-small Cell Lung Carcinoma J. Biol. Chem., January 11, 2008; 283(2): 963 - 976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Nikolic, M. C. Gong, J. Turk, and S. R. Post Class A Scavenger Receptor-mediated Macrophage Adhesion Requires Coupling of Calcium-independent Phospholipase A2 and 12/15-Lipoxygenase to Rac and Cdc42 Activation J. Biol. Chem., November 16, 2007; 282(46): 33405 - 33411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Stapleton, Adam. G. Goodwill, M. E. James, and J. C. Frisbee Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1110 - R1119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Y. Zhu, E. Daghini, A. R. Chade, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Simvastatin Prevents Coronary Microvascular Remodeling in Renovascular Hypertensive Pigs J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1209 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Bolick, A. M. Whetzel, M. Skaflen, T. L. Deem, J. Lee, and C. C. Hedrick Absence of the G Protein-Coupled Receptor G2A in Mice Promotes Monocyte/Endothelial Interactions in Aorta Circ. Res., March 2, 2007; 100(4): 572 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kimura, H. Tomura, C. Mogi, A. Kuwabara, A. Damirin, T. Ishizuka, A. Sekiguchi, M. Ishiwara, D.-S. Im, K. Sato, et al. Role of Scavenger Receptor Class B Type I and Sphingosine 1-Phosphate Receptors in High Density Lipoprotein-induced Inhibition of Adhesion Molecule Expression in Endothelial Cells J. Biol. Chem., December 8, 2006; 281(49): 37457 - 37467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Pang, A. Lin, M. Holford, B. E. Enerson, B. Lu, M. P. Lawton, E. Floyd, and H. Zhao Pathway analysis using random forests classification and regression Bioinformatics, August 15, 2006; 22(16): 2028 - 2036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Funk Lipoxygenase Pathways as Mediators of Early Inflammatory Events in Atherosclerosis. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1204 - 1206. [Full Text] [PDF]
|
|
|
|
|
|
D. T. Bolick, S. Srinivasan, A. Whetzel, L. C. Fuller, and C. C. Hedrick 12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E-Deficient Mice Through Activation of RhoA and NF-{kappa}B Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1260 - 1266. [Abstract] [Full Text] [PDF]
|
|