doi: 10.1161/01.CIR.0000159336.31613.31
(Circulation. 2005;111:1530-1536.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Inflammation and Endothelial Function
Direct Vascular Effects of Human C-Reactive Protein on Nitric Oxide Bioavailability
From the Centre for Clinical Pharmacology and Therapeutics, BHF Laboratories (B.R.C., R.J.M., P.V., A.D.H.); Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus (G.M.H., J.R.G., M.B.P.); Vascular Physiology Unit, Institute of Child Health (C.S., J.E.D.); and Bloomsbury Institute for Intensive Care Medicine (R.P.S., M.S.), Department of Medicine, University College London; all in London, United Kingdom.
Correspondence to Dr Aroon D. Hingorani, Centre for Clinical Pharmacology, BHF Laboratories, Department of Medicine, University College London, The Rayne Building, 5 University St, London WC1E 6JJ, United Kingdom. E-mail a.hingorani{at}ucl.ac.uk
Received June 14, 2004; revision received October 12, 2004; accepted November 18, 2004.
Background— Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity.
Methods and Results— The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure.
Conclusions— Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP.
Key Words: endothelium • inflammation • nitric oxide
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