Predominance of a proinflammatory phenotype in monocyte-derived macrophages from subjects with low plasma HDL-cholesterol.
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.


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) gamma 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 PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta 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 1beta, interleukin 8, and tumor necrosis factor alpha 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 PPARgamma and PPARdelta.
Sarov-Blat
Lea
L
University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada.
Kiss
Robert S
RS
Haidar
Bassam
B
Kavaslar
Nihan
N
Jaye
Michael
M
Bertiaux
Melissa
M
Steplewski
Klaudia
K
Hurle
Mark R
MR
Sprecher
Dennis
D
McPherson
Ruth
R
Marcel
Yves L
YL
D050197:Atherosclerosis / Q000097:blood / Q000209:etiology; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood / Q000172:deficiency*; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007009:Hypolipoproteinemias / Q000097:blood* / Q000150:complications / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D046228:Microarray Analysis; D009154:Mutation; D047494:PPAR delta / Q000096:biosynthesis / Q000235:genetics*; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics*; D000070780:Perilipin-2; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D015415:Biomarkers; D008076:Cholesterol, HDL; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D053583:Interleukin-1beta; D016209:Interleukin-8; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D047494:PPAR delta; D047495:PPAR gamma; D000070780:Perilipin-2; D014409:Tumor Necrosis Factor-alpha; D012313:RNA