Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability.
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.


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.
Clapp
Brian R
BR
Centre for Clinical Pharmacology and Therapeutics, BHF Laboratories, University College London, London, United Kingdom.
Hirschfield
Gideon M
GM
Storry
Clare
C
Gallimore
J Ruth
JR
Stidwill
Ray P
RP
Singer
Mervyn
M
Deanfield
John E
JE
MacAllister
Raymond J
RJ
Pepys
Mark B
MB
Vallance
Patrick
P
Hingorani
Aroon D
AD
D000818:Animals; D001158:Arteries; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D006136:GTP Cyclohydrolase / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D002097:C-Reactive Protein; D006136:GTP Cyclohydrolase