Circulation. 2002;106:913-919
Published online before print July 29, 2002, doi: 10.1161/01.CIR.0000029802.88087.5E
Published online before print July 29, 2002, doi: 10.1161/01.CIR.0000029802.88087.5E
(Circulation. 2002;106:913.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
A Self-Fulfilling Prophecy
C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits Angiogenesis
From the Division of Cardiac Surgery (S.V., C.-H.W., S.-H.L., P.W.M.F., M.V.B., B.D., R.D.W., R.-K.L., D.A.G.M.), Toronto General Hospital, University of Toronto, Toronto, Canada; Division of Neurosurgery (A.S.D), University of Virginia, Charlottesville; and the Division of Cardiology (D.J.S.), St Michael’s Hospital, University of Toronto, Toronto, Canada.
Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, 14 EN-215, 200 Elizabeth St, Toronto General Hospital, Toronto, ON, Canada M5G 2C4. (e-mail subodh.verma{at}sympatico.ca); or Donald A.G. Mickle, MD, University of Toronto, Toronto, Canada.
Background— Given the central importance of nitric oxide (NO) in the development and clinical course of cardiovascular diseases, we sought to determine whether the powerful predictive value of C-reactive protein (CRP) might be explained through an effect on NO production.
Methods and Results— Endothelial cells (ECs) were incubated with recombinant CRP (0 to 100 µg/mL, 24 hours), and NO and cyclic guanosine monophosphate (cGMP) production was assessed. The effects of CRP on endothelial NO synthase (eNOS) protein, mRNA expression, and mRNA stability were also examined. In a separate study, the effects of CRP (25 µg/mL) on EC cell survival, apoptosis, and in vitro angiogenesis were evaluated. Incubation of ECs with CRP resulted in a significant inhibition of basal and stimulated NO release, with concomitant reductions in cGMP production. CRP caused a marked downregulation of eNOS mRNA and protein expression. Actinomycin D studies suggested that eNOS downregulation was related to decreased mRNA stability. In conjunction with a decrease in NO production, CRP inhibited both basal and vascular endothelial growth factor–stimulated angiogenesis as assessed by EC migration and capillary-like tube formation. CRP did not induce EC survival but did, however, promote apoptosis in a NO-dependent fashion.
Conclusions— CRP, at concentrations known to predict adverse vascular events, directly quenches the production of the NO, in part, through posttranscriptional effect on eNOS mRNA stability. Diminished NO bioactivity, in turn, inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. Through decreasing NO synthesis, CRP may facilitate the development of diverse cardiovascular diseases. Risk reduction strategies designed to lower plasma CRP may be effective by improving NO bioavailability.
Key Words: angiogenesis • nitric oxide • interleukins • protein, C-reactive • cells
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 Y. Higashi, C. Goto, D. Jitsuiki, T. Umemura, K. Nishioka, T. Hidaka, H. Takemoto, S. Nakamura, J. Soga, K. Chayama, et al. Periodontal Infection Is Associated With Endothelial Dysfunction in Healthy Subjects and Hypertensive Patients Hypertension, February 1, 2008; 51(2): 446 - 453. [Abstract] [Full Text] [PDF]
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|
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|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
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|
|
|
|
|
|
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|
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|
|
|
|
 |
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 M. Hermann and F. Ruschitzka Novel anti-inflammatory drugs in hypertension Nephrol. Dial. Transplant., April 1, 2006; 21(4): 859 - 864. [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 D. M. Mannino, G. Watt, D. Hole, C. Gillis, C. Hart, A. McConnachie, G. Davey Smith, M. Upton, V. Hawthorne, D. D. Sin, et al. The natural history of chronic obstructive pulmonary disease. Eur. Respir. J., March 1, 2006; 27(3): 627 - 643. [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 R. Ullegaddi, H. J. Powers, and S. E. Gariballa Antioxidant Supplementation With or Without B-Group Vitamins After Acute Ischemic Stroke: A Randomized Controlled Trial JPEN J Parenter Enteral Nutr, March 1, 2006; 30(2): 108 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sander, C. Schulze-Horn, H. Bickel, H. Gnahn, E. Bartels, and B. Conrad Combined Effects of Hemoglobin A1c and C-Reactive Protein on the Progression of Subclinical Carotid Atherosclerosis: The INVADE Study Stroke, February 1, 2006; 37(2): 351 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khera, J. A. de Lemos, R. M. Peshock, H. S. Lo, H. G. Stanek, S. A. Murphy, F. H. Wians Jr, S. M. Grundy, and D. K. McGuire Relationship Between C-Reactive Protein and Subclinical Atherosclerosis: The Dallas Heart Study Circulation, January 3, 2006; 113(1): 38 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. Futterman and L. Lemberg Regular Physical Exercise Reduces Cardiovascular Risks Am. J. Crit. Care., January 1, 2006; 15(1): 99 - 102. [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3553 - 3562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Mineo, A. K. Gormley, I. S. Yuhanna, S. Osborne-Lawrence, L. L. Gibson, L. Hahner, R. V. Shohet, S. Black, J. E. Salmon, D. Samols, et al. Fc{gamma}RIIB Mediates C-Reactive Protein Inhibition of Endothelial NO Synthase Circ. Res., November 25, 2005; 97(11): 1124 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. De Servi, M. Mariani, G. Mariani, and A. Mazzone C-Reactive Protein Increase in Unstable Coronary Disease: Cause or Effect? J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1496 - 1502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Sun, T. Koike, T. Ichikawa, K. Hatakeyama, M. Shiomi, B. Zhang, S. Kitajima, M. Morimoto, T. Watanabe, Y. Asada, et al. C-Reactive Protein in Atherosclerotic Lesions: Its Origin and Pathophysiological Significance Am. J. Pathol., October 1, 2005; 167(4): 1139 - 1148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Cirillo, P. Golino, P. Calabro, G. Cali, M. Ragni, S. De Rosa, G. Cimmino, M. Pacileo, R. De Palma, L. Forte, et al. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation Cardiovasc Res, October 1, 2005; 68(1): 47 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Singh, S. Devaraj, and I. Jialal C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells: Evidence that C-Reactive Protein Is a Procoagulant Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2216 - 2221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakakuki, M. Ito, H. Iwasaki, Y. Kureishi, R. Okamoto, N. Moriki, M. Kongo, S. Kato, N. Yamada, N. Isaka, et al. Rho/Rho-Kinase Pathway Contributes to C-Reactive Protein-Induced Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2088 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mittermayer, J. Pleiner, G. Schaller, S. Zorn, K. Namiranian, S. Kapiotis, G. Bartel, M. Wolfrum, M. Brugel, J. Thiery, et al. Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1752 - H1757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Anand, R. Latini, V. G. Florea, M. A. Kuskowski, T. Rector, S. Masson, S. Signorini, P. Mocarelli, A. Hester, R. Glazer, et al. C-Reactive Protein in Heart Failure: Prognostic Value and the Effect of Valsartan Circulation, September 6, 2005; 112(10): 1428 - 1434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. T. Bloomgarden Inflammation, Atherosclerosis, and Aspects of Insulin Action Diabetes Care, September 1, 2005; 28(9): 2312 - 2319. [Full Text] [PDF]
|
|
|
|
|
|
S. B. Schwedler, K. Amann, K. Wernicke, A. Krebs, M. Nauck, C. Wanner, L. A. Potempa, and J. Galle Native C-Reactive Protein Increases Whereas Modified C-Reactive Protein Reduces Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, August 16, 2005; 112(7): 1016 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Thanyasiri, D. S. Celermajer, and M. R. Adams Endothelial dysfunction occurs in peripheral circulation patients with acute and stable coronary artery disease Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H513 - H517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
 |
|
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