Native C-reactive protein induces endothelial dysfunction in ApoE-/- mice: implications for iNOS and reactive oxygen species.
OBJECTIVE
In addition to being a risk marker for cardiovascular disease, recent data suggests that C-reactive protein (CRP) induces endothelial dysfunction and promotes oxidative stress. We evaluated the effects of two conformers of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) on vessel function and production of reactive oxygen species (ROS) in an in-vivo model of atherosclerosis.


RESULTS
Female ApoE(-/-) mice, fed a "western-type" diet, were treated with either human nCRP or mCRP (2.5mg/kg s.c., weekly) or saline for 8 weeks. Endothelium-dependent and endothelium-independent vascular functions were assessed in isolated aortic rings under isometric conditions. Production of ROS in aortic rings was measured by electron spin resonance (ESR). Endothelium-dependent relaxation was impaired in nCRP-treated but not in mCRP-treated ApoE(-/-) mice. This impairment was reversed by preincubation with an inhibitor of inducible nitric oxide synthase (iNOS). Endothelium-independent relaxation, and iNOS and endothelial NOS (eNOS) protein expressions were similar among all groups. ESR experiments revealed lesser amounts of superoxide in the nCRP group as compared to the saline group, which is consistent with an increased transformation of NO to peroxynitrite.


CONCLUSIONS
nCRP can facilitate cardiovascular disease through impairment of endothelium-dependent vasoreactivity, in a manner that involves increased iNOS activity and a potential for increased peroxynitrite formation.
Department of Medicine I, University Hospital Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Pelleas@t-online.de
Susanne B
SB
Schwedler
Peter J
PJ
Kuhlencordt
P Padmapriya
PP
Ponnuswamy
Gencay
G
Hatiboglu
Thomas
T
Quaschning
Julian
J
Widder
Christoph
C
Wanner
Lawrence A
LA
Potempa
Jan
J
Galle
D000818:Animals; D001011:Aorta / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000235:genetics*; D002097:C-Reactive Protein / Q000502:physiology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D002097:C-Reactive Protein; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III