Hyperglycemia potentiates the proatherogenic effects of C-reactive protein: reversal with rosiglitazone.
Accumulating evidence suggests that C-reactive protein (CRP), at concentrations known to predict diverse vascular insults, directly promotes endothelial cell activation, uncovering a proatherosclerotic and proinflammatory phenotype. In the present study, we hypothesized that (a). hyperglycemia would serve to exaggerate the proatherogenic effects of CRP and (b). the PPARgamma agonist, rosiglitazone would attenuate this effect. Human saphenous vein endothelial cells were studied under the following conditions (n= 10 per group): control, human recombinant CRP (25 microg/ml, 24 h), hyperglycemia (25 mM, 24 h) and hyperglycemia + CRP. In each case, the effects of co-incubation with rosiglitazone (1 microM) were evaluated. Nitric oxide and endothelin-1 release from endothelial cells was quantified, in addition to the expression of adhesion molecules and monocyte chemoattractant chemokine (MCP-1). Incubation of endothelial cells with CRP increased endothelin-1 production, and upregulated adhesion molecule and MCP-1 expression. These proatherogenic effects of CRP were potentiated in the presence of hyperglycemia. CRP also decreased endothelial nitric oxide release, and this effect remained unchanged by hyperglycemia. Importantly, the PPARgamma agonist, rosiglitazone, attenuated the proatherogenic effects of CRP under both basal and hyperglycemic conditions. The direct proatherogenic actions of CRP are exaggerated in the hyperglycemic milieu, and attenuated by rosiglitazone. Elevated CRP levels in patients with diabetes may serve to uncover a severe proatherogenic phenotype.
Verma
Subodh
S
Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, 14 EN-215, 200 Elizabeth Street, Toronto, Ont, Canada M5G 2C4. subodh.verma@sympatico.ca
Wang
Chao-Hung
CH
Weisel
Richard D
RD
Badiwala
Mitesh V
MV
Li
Shu-Hong
SH
Fedak
Paul W M
PW
Li
Ren-Ke
RK
Mickle
Donald A G
DA
D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000077154:Rosiglitazone; D012501:Saphenous Vein / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002097:C-Reactive Protein