Impaired endothelial function in C-reactive protein overexpressing mice.
Increasing evidence suggests that the inflammatory biomarker, C-reactive protein (CRP), may play a causal role in the development and progression of atherothrombosis. Since endothelial dysfunction is an early and integral component of atherosclerosis, we hypothesized that endothelial homeostasis would be impaired in CRP-overexpressing CRP transgenic (CRPtg) mice. Male CRPtg and wild-type mice were injected thrice over 2 weeks with vehicle or turpentine to induce the inflammation-sensitive CRP transgene. Serum human CRP levels in turpentine-treated CRPtg mice was 276.28 +/- 95.7 microg/ml. Human CRP was undetectable in the sera of wild-type mice and present at only low levels (1.41 +/- 0.2 microg/ml) in vehicle-treated CRPtg mice (n=6-8 mice/group). Aortic segments from turpentine-induced CRP-overexpressing CRPtg mice demonstrated impaired endothelium-dependent responses to acetylcholine vs. those from vehicle-treated CRPtg controls (57.1 +/- 9.5% vs. 85.0 +/- 5.0%, P<0.05, n=6). Nitric oxide release as well as phosphorylated eNOS protein expression from isolated aortic segments of CRPtg mice overexpressing CRP were markedly reduced compared to that from vehicle-treated controls. Masson's trichrome staining revealed increased perivascular fibrosis in CRP-overexpressing CRPtg mice. CRP overexpression was also associated with augmented aortic endothelial staining for VCAM-1 and MCP-1 and enhanced macrophage infiltration. Mice overexpressing the human CRP gene exhibit endothelial dysfunction, possibly via reduced NO bioavailability, with resultant changes in vascular structure. These data further support a role for CRP in mediating endothelial dysfunction.
Teoh
Hwee
H
Division of Cardiac Surgery, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Quan
Adrian
A
Lovren
Fina
F
Wang
Guilin
G
Tirgari
Sam
S
Szmitko
Paul E
PE
Szalai
Alexander J
AJ
Ward
Michael E
ME
Verma
Subodh
S
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D014425:Turpentine
D015415:Biomarkers; D009569:Nitric Oxide; D002097:C-Reactive Protein; D014425:Turpentine