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(Circulation Research. 2007;100:1452.)
© 2007 American Heart Association, Inc.

Molecular Medicine

C-Reactive Protein Downregulates Endothelial NO Synthase and Attenuates Reendothelialization In Vivo in Mice

Randall Schwartz^*, Sherri Osborne-Lawrence^*, Lisa Hahner, Linda L. Gibson, Andrew K. Gormley, Wanpen Vongpatanasin, Weifei Zhu, R. Ann Word, Divya Seetharam, Steven Black, David Samols, Chieko Mineo, Philip W. Shaul

From the Departments of Pediatrics (R.S., S.O.-L., L.H., L.L.G., A.K.G., W.Z., D.S., C.M., P.W.S.), Internal Medicine (W.V.), and Obstetrics and Gynecology (R.A.W.), University of Texas Southwestern Medical Center, Dallas; 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 75390. E-mail philip.shaul{at}utsouthwestern.edu

C-reactive protein (CRP) is an acute-phase reactant that is positively associated with cardiovascular disease risk and endothelial dysfunction. In cell culture, CRP decreases the expression of endothelial NO synthase (eNOS), which regulates diverse endothelial cell (EC) functions including migration. To determine whether CRP alters EC gene expression and phenotype in vivo, we studied CF1 transgenic mice expressing rabbit CRP (CF1-CRP) regulated by the phosphoenolpyruvate carboxykinase promoter such that levels could be altered by changing carbohydrate intake. Compared with CF1 controls with CRP of <1 µg/mL, carotid artery reendothelialization after perivascular electric injury was blunted in CF1-CRP mice, with CRP levels as low as 9 µg/mL. eNOS mRNA and enzyme abundance in carotid arteries was also blunted by CRP at 9 µg/mL in vivo, and ex vivo studies of isolated arteries showed that this occurs via direct action on the endothelium. The impaired reendothelialization with CRP was mimicked by NOS antagonism in CF1 mice; conversely, in cultured ECs CRP attenuation of migration was prevented by exogenous NO. Studies of EC transfected with human eNOS 5' flanking sequence fused to luciferase indicated that CRP decreases eNOS gene transcription. Both mutagenesis and electrophoretic mobility shift assays further revealed that CRP-responsive elements reside within the first 79 bp of the eNOS promoter. Thus, CRP downregulates eNOS and attenuates reendothelialization in vivo in mice, and this action of CRP on eNOS is mediated at the level of gene transcription.

Key Words: C-reactive protein • endothelial NO synthase • reendothelialization

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