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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1115.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Predominance of a Proinflammatory Phenotype in Monocyte-Derived Macrophages From Subjects With Low Plasma HDL-Cholesterol

Lea Sarov-Blat; Robert S. Kiss; Bassam Haidar; Nihan Kavaslar; Michael Jaye; Melissa Bertiaux; Klaudia Steplewski; Mark R. Hurle; Dennis Sprecher; Ruth McPherson; Yves L. Marcel

From the Lipoprotein and Atherosclerosis Research Group University of Ottawa Heart Institute (R.S.K., B.H., N.K., R.M., Y.L.M.), the Departments of Pathology and Laboratory Medicine (Y.L.M.) and of Medicine, Division of Cardiology (R.M.), University of Ottawa, Ontario, Canada; and GlaxoSmithKline (L.S.-B., M.J., M.B., K.S., M.R.H., D.S.), King of Prussia, Pa.

Correspondence to Y.L. Marcel or R. McPherson, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. E-mail ylmarcel{at}ottawaheart.ca or rmcpherson@ottawaheart.ca

Objective— Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation.

Methods and Results— Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPAR, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPAR expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1ß, interleukin 8, and tumor necrosis factor were highly increased in low HDL-C subjects.

Conclusions— The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPAR and PPAR.

We demonstrate that cholesterol loaded monocyte-derived macrophages from low HDL-C subjects exhibit a complex inflammatory gene response, related to altered expression of PPAR, PPAR, and a cluster of metallothionein genes. Our results suggest that a heightened macrophage inflammatory response may contribute to the pathophysiological consequences of HDL deficiency.

Key Words: lipoproteins • inflammation • cholesterol • genes