Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo.
OBJECTIVE
Elevated C-reactive protein (CRP) levels are associated with increased cardiovascular events and endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) activity in endothelial cells and inhibits endothelium-dependent nitric oxide (NO)-mediated vasodilation in vitro. Herein, we examined the effect of in vivo administration of CRP on endothelial function and underlying mechanisms in a valid animal model.


METHODS
Sprague-Dawley rats were injected intraperitoneally daily for 3 days with human CRP or human serum albumin (HuSA) at 20 mg/kg body weight. On day 4, mesenteric arterioles were isolated and pressurized for vasomotor study and aortic tissue was subjected to biochemical and molecular analysis.


RESULTS
Dilation of mesenteric arterioles to acetylcholine but not to sodium nitroprusside was significantly reduced following CRP treatment. The eNOS activity, eNOS dimer/monomer ratio, tetrahydrobiopterin levels, and protein expression of GTPCH1 were significantly lower in aortic tissue homogenates from CRP-treated than HuSA-treated rats. CRP treatment also resulted in increased dihydroethidium staining for superoxide in aortic endothelium and membrane translocation of p47phox, a regulatory subunit of NADPH oxidase.


CONCLUSIONS
Our data provide novel evidence for the detrimental action of CRP in vivo by impairing eNOS-dependent vasodilation and uncoupling of eNOS.
Hein
Travis W
TW
Department of Surgery, Scott & White Memorial Hospital, College of Medicine, Texas A&M Health Science Center, Temple, TX, USA.
Singh
Uma
U
Vasquez-Vivar
Jeannette
J
Devaraj
Sridevi
S
Kuo
Lih
L
Jialal
Ishwarlal
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002097:C-Reactive Protein / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D023421:Models, Animal; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D013481:Superoxides; D009599:Nitroprusside; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000109:Acetylcholine