A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis.
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.


RESULTS
Endothelial cells (ECs) were incubated with recombinant CRP (0 to 100 microg/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 microg/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.
Verma
Subodh
S
Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Canada. subodh.verma@sympatico.ca
Wang
Chao-Hung
CH
Li
Shu-Hong
SH
Dumont
Aaron S
AS
Fedak
Paul W M
PW
Badiwala
Mitesh V
MV
Dhillon
Bikramjit
B
Weisel
Richard D
RD
Li
Ren-Ke
RK
Mickle
Donald A G
DA
Stewart
Duncan J
DJ
D017209:Apoptosis; D002097:C-Reactive Protein / Q000494:pharmacology* / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger; D009569:Nitric Oxide; D002097:C-Reactive Protein; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP