C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production.
OBJECTIVE
Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with systemic vascular disorders. In addition, clinical studies have implicated that elevated CRP is an independent risk factor for diabetic retinopathy and age-related macular degeneration. However, the direct effect of CRP on ocular microvascular reactivity remains unknown. The authors examined whether CRP can affect endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles and whether oxidative stress and distinct protein kinase signaling pathways are involved in the CRP-mediated effect.


METHODS
Porcine retinal arterioles (internal diameter, 71 +/- 2 microm) were isolated and pressurized without flow for in vitro study. Diameter changes were recorded using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production.


RESULTS
Intraluminal treatment with a clinically relevant concentration of CRP (7 microg/mL, 60 minutes) significantly attenuated arteriolar dilation to endothelium-dependent NO-mediated agonists bradykinin and A23187 but not to endothelium-independent NO donor sodium nitroprusside. In the presence of superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor apocynin, p38 kinase inhibitor SB203580, simvastatin, or Rho-kinase inhibitor Y-27632, the detrimental effect of CRP on bradykinin-induced dilation was prevented. DHE staining showed that CRP produced TEMPOL-sensitive superoxide production in the arteriolar endothelium.


CONCLUSIONS
CRP inhibits endothelium-dependent NO-mediated dilation in retinal arterioles by producing superoxide from NAD(P)H oxidase, which appears to be linked with p38 kinase and RhoA/Rho-kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP can potentially facilitate the development of retinal vascular diseases. In addition, statins are beneficial by preserving endothelial function, possibly through inactivation of the RhoA/Rho-kinase pathway.
Nagaoka
Taiji
T
Department of Ophthalmology, Scott & White Eye Institute, Temple, TX 76504, USA. nagaoka@asahikawa-med.ac.jp
Kuo
Lih
L
Ren
Yi
Y
Yoshida
Akitoshi
A
Hein
Travis W
TW
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002097:C-Reactive Protein / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D004108:Dilatation, Pathologic / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D000001:Calcimycin; D002097:C-Reactive Protein; D019255:NADPH Oxidases; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001920:Bradykinin