This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/11/1124    most recent 01.RES.0000194323.77203.fev1 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 Mineo, C. Articles by Shaul, P. W. Search for Related Content PubMed PubMed Citation Articles by Mineo, C. Articles by Shaul, P. W. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors Risk Factors Cell signalling/signal transduction

(Circulation Research. 2005;97:1124.)
© 2005 American Heart Association, Inc.

Molecular Medicine

FcRIIB Mediates C-Reactive Protein Inhibition of Endothelial NO Synthase

Chieko Mineo^*, Andrew K. Gormley^*, Ivan S. Yuhanna, Sherri Osborne-Lawrence, Linda L. Gibson, Lisa Hahner, Ralph V. Shohet, Steven Black, Jane E. Salmon, David Samols, David R. Karp, Gail D. Thomas, Philip W. Shaul

From the Departments of Pediatrics (C.M., A.K.G., I.S.Y., S.O.-L., L.L.G., L.H., P.W.S.) and Internal Medicine (R.V.S., D.R.K., G.D.T.), University of Texas Southwestern Medical Center, Dallas; Department of Medicine (J.E.S.), Cornell University Weill Medical College, New York, NY; and Department of Biochemistry (S.B., D.S.), Case Western Reserve University School of Medicine, Cleveland, Ohio.

Correspondence to Philip W. Shaul, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX. E-mail philip.shaul{at}utsouthwestern.edu

C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk and endothelial dysfunction. Whether CRP has direct actions on endothelium and the mechanisms underlying such actions are unknown. Here we show in cultured endothelium that CRP prevents endothelial NO synthase (eNOS) activation by diverse agonists, resulting in the promotion of monocyte adhesion. CRP antagonism of eNOS occurs nongenomically and is attributable to blunted eNOS phosphorylation at Ser1179. Okadaic acid or knockdown of PP2A by short-interference RNA reverses CRP antagonism of eNOS, indicating a key role for the phosphatase. Aggregated IgG, the known ligand for Fc receptors, causes parallel okadaic acid–sensitive loss of eNOS function, FcRIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires FcRIIB. In FcRIIB^+/+ mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in FcRIIB^–/– mice. Thus FcRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.

Key Words: C-reactive protein • endothelial NO synthase • Fc receptor • PP2A

This article has been cited by other articles:

				T. Nagaoka, L. Kuo, Y. Ren, A. Yoshida, and T. W. Hein C-Reactive Protein Inhibits Endothelium-Dependent Nitric Oxide-Mediated Dilation of Retinal Arterioles via Enhanced Superoxide Production Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 2053 - 2060. [Abstract] [Full Text] [PDF]

				D. Xing, F. G. Hage, Y.-F. Chen, M. A. McCrory, W. Feng, G. A. Skibinski, E. Majid-Hassan, S. Oparil, and A. J. Szalai Exaggerated Neointima Formation in Human C-Reactive Protein Transgenic Mice Is IgG Fc Receptor Type I (Fc{gamma}RI)-Dependent Am. J. Pathol., January 1, 2008; 172(1): 22 - 30. [Abstract] [Full Text] [PDF]

				H. Teoh, A. Quan, and S. Verma Does C-reactive protein predict saphenous vein graft patency? J. Thorac. Cardiovasc. Surg., August 1, 2007; 134(2): 277 - 279. [Full Text] [PDF]

				R. Jain, P. W. Shaul, Z. Borok, and B. C. Willis Endothelin-1 Induces Alveolar Epithelial-Mesenchymal Transition through Endothelin Type A Receptor-Mediated Production of TGF-beta1 Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 38 - 47. [Abstract] [Full Text] [PDF]

				E. Grad, M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E. R. Edelman, and H. D. Danenberg Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H489 - H495. [Abstract] [Full Text] [PDF]

				P. Kumar, Q. Wu, K. L. Chambliss, I. S. Yuhanna, S. M. Mumby, C. Mineo, G. G. Tall, and P. W. Shaul Direct Interactions with G{alpha}i and G{beta}{gamma} Mediate Nongenomic Signaling by Estrogen Receptor {alpha} Mol. Endocrinol., June 1, 2007; 21(6): 1370 - 1380. [Abstract] [Full Text] [PDF]

				R. Schwartz, S. Osborne-Lawrence, L. Hahner, L. L. Gibson, A. K. Gormley, W. Vongpatanasin, W. Zhu, R. A. Word, D. Seetharam, S. Black, et al. C-Reactive Protein Downregulates Endothelial NO Synthase and Attenuates Reendothelialization In Vivo in Mice Circ. Res., May 25, 2007; 100(10): 1452 - 1459. [Abstract] [Full Text] [PDF]

				R. J. Bisoendial, J. J. P. Kastelein, S. L. M. Peters, J. H. M. Levels, R. Birjmohun, J. I. Rotmans, D. Hartman, J. C. M. Meijers, M. Levi, and E. S. G. Stroes Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects J. Lipid Res., April 1, 2007; 48(4): 952 - 960. [Abstract] [Full Text] [PDF]

				W. Vongpatanasin, G. D. Thomas, R. Schwartz, L. A. Cassis, S. Osborne-Lawrence, L. Hahner, L. L. Gibson, S. Black, D. Samols, and P. W. Shaul C-Reactive Protein Causes Downregulation of Vascular Angiotensin Subtype 2 Receptors and Systolic Hypertension in Mice Circulation, February 27, 2007; 115(8): 1020 - 1028. [Abstract] [Full Text] [PDF]

				C. Kishimoto A Novel Approach to the Suppression of Atherosclerosis by Fc{gamma} Receptor Blockade Circ. Res., November 24, 2006; 99(11): 1154 - 1155. [Full Text] [PDF]

				P. Hernandez-Vargas, G. Ortiz-Munoz, O. Lopez-Franco, Y. Suzuki, J. Gallego-Delgado, G. Sanjuan, A. Lazaro, V. Lopez-Parra, L. Ortega, J. Egido, et al. Fc{gamma} Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice Circ. Res., November 24, 2006; 99(11): 1188 - 1196. [Abstract] [Full Text] [PDF]

				H. Fujii, S.-H. Li, P. E. Szmitko, P. W.M. Fedak, and S. Verma C-Reactive Protein Alters Antioxidant Defenses and Promotes Apoptosis in Endothelial Progenitor Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2476 - 2482. [Abstract] [Full Text] [PDF]

				S. Devaraj, B. Davis, S. I. Simon, and I. Jialal CRP promotes monocyte-endothelial cell adhesion via Fc{gamma} receptors in human aortic endothelial cells under static and shear flow conditions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1170 - H1176. [Abstract] [Full Text] [PDF]

				B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal The Verdict Is Still Out Circulation, May 2, 2006; 113(17): 2128 - 2151. [Full Text] [PDF]

				C. Mineo and P. W. Shaul Circulating cardiovascular disease risk factors and signaling in endothelial cell caveolae Cardiovasc Res, April 1, 2006; 70(1): 31 - 41. [Abstract] [Full Text] [PDF]

				I. Fleming Segregation and integration: Roles played by caveolae and caveolins in the cardiovascular system Cardiovasc Res, March 1, 2006; 69(4): 784 - 787. [Full Text] [PDF]

				C. Kishimoto, K. Shioji, and Z. Yuan Fc{gamma}IIB and Cardiovascular Inflammatory Disease Circ. Res., February 17, 2006; 98(3): e26 - e26. [Full Text] [PDF]