Modulation of C-Reactive Protein-Mediated MCP-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs

Vincenzo Pasceri, Jed Chang, James T. Willerson, Edward T.H. Yeh*

Department of Cardiology (E.T.H.Y.), University of Texas-M.D. Anderson Cancer Center, Houston, Texas, Department of Internal Medicine (V.P., J.T.W., E.T.H.Y.), University of Texas Health Science Center, Houston, Texas; and the Texas Heart Institute (V.P., J.T.W., E.T.H.Y.), St. Luke’s Episcopal Hospital, Houston, Texas

*Corresponding author

Background We have previously shown that C-reactive protein (CRP) directly induces adhesion molecule expression by endothelial cells. However, the effects of CRP on chemokine expression by endothelial cells are not known.

Methods and Results We tested the effects of CRP on production of the chemokines, macrophage chemoattractant protein-1(MCP-1) and RANTES, in cultured human umbilical vein endothelial cells (HUVEC). Secretion of chemokines was assessed by ELISA. Incubation with 100 mg/mL of recombinant human CRP induced a 7 fold increase in MCP-1, but no change in RANTES secretion. We showed that the effect of CRP on MCP-1 was present even at 5 mg/mL CRP, with stepwise increase as the CRP concentration was increased to 10, 50 and 100 mg/mL. The effect of C-reactive protein on MCP-1 induction was not influenced by aspirin (at concentration up to 1 mM), but was significantly inhibited by simvastatin 5 mM. The PPARa activators, fenofibrate (100 mM) and Wy-14649 (100 mM) almost completely abolished the induction of MCP-1, while the PPARg activator, ciglitazone had only a moderate effect.

Conclusions Thus, CRP not only induces the expression of adhesion molecules, but also relevant chemokines in human endothelial cells, providing an attractive milieu for recruiting circulating monocytes to the arterial wall. These results further strengthen the role of CRP in the pathogenesis of vascular inflammation and, likely, atherosclerosis, and provide a crucial insight into a novel mechanism of action of anti-atherosclerosis drugs, such as simvastatin and fenofibrate.