C-reactive protein enhances macrophage lipoprotein lipase expression

Abstract

High serum levels of C-reactive protein (CRP), a strong predictor of cardiovascular events, are documented in patients with type 2 diabetes. Accumulating evidence suggests that CRP could directly promote arterial damage. To determine the role of CRP in diabetic atherosclerosis, we examined the effect of CRP on the expression of macrophage lipoprotein lipase (LPL), a proatherogenic molecule upregulated in type 2 diabetes. Treatment of human macrophages with native CRP increased, in a dose-and timedependent manner, LPL protein expression and secretion. Modified CRP reproduced these effects. Preincubation of human macrophages with antioxidants, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) inhibitors prevented CRP-induced LPL expression. Exposure of human macrophages to CRP further increased intracellular reactive oxygen species generation, classic PKC isozymes expression, and extracellular signal-regulated protein kinase 1/2 phosphorylation. In CRP-treated J774 macrophages, increased macrophage LPL mRNA levels and enhanced binding of nuclear proteins to the activated protein-1 (AP-1)-enhancing element were observed. These effects were prevented by antioxidants, as well as by PKC, MAPK, and AP-1 inhibitors. These data show for the first time that CRP directly increases macrophage LPL expression and secretion. Given the predominant role of macrophage LPL in atherogenesis, LPL might represent a novel factor underlying the adverse effect of CRP on the diabetic vasculature.-Maingrette, F., L. Li, and G. Renier. C-reactive protein enhances macrophage lipoprotein lipase expression. J. Lipid Res. 2008Res. . 49: 1926Res. -1935 Since the hypothesis that inflammation might be an accomplice in the pathogenesis of atherosclerosis and type 2 diabetes was first proposed, many epidemiological and clinical studies have shown that circulating markers of inflammation predict the risk of future cardiovascular (CV) events and type 2 diabetes and that an ongoing acute phase response is present in patients with type 2 diabetes (1). In addition to being a CV risk marker (2, 3), C-reactive protein (CRP) could also make a direct contribution to the atherosclerotic process. Supporting this possibility, it has been shown that CRP is present in the plaque (4) and that exposure of cultured vascular cells to CRP leads to various proinflammatory and proatherogenic effects. Among the cell types found in the lesion, monocytes/macrophages have essential functions in all phases of atherosclerosis. Interaction of CRP with these cells induces an increase in the secretion of inflammatory mediators such as cytokines and chemokines (5, 6). Additional effects of CRP on monocytes/macrophages include induction of colony stimulating factor (CSF), matrix metalloproteinase (MMP), nitric oxide, and tumoricidal activity (7-10). Most importantly, CRP also appears to promote infiltration of monocytes into the vessel wall (11) and their subsequent development into foam cells (12).Lipoprotein lipase (LPL) is a key enzyme in the hydro...

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