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

Abstract

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 1␤, 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␦.

Serum, but not monocyte macrophage foam cells derived from low HDL-C subjects, displays reduced cholesterol efflux capacity

“…Although about 30% of low-HDL subjects exhibited cellular cholesterol efflux defects, the majority of these subjects did not harbor functional mutations in ABCA1. A recent observation that the activated proinflammatory state of the monocytes and macrophages in low-HDL subjects may contribute to the pathophysiological consequences of low HDL prompted us to test for this in our sample (23). In the present study, quantitative RT-PCR analysis for relative Fig.…”

“…Relative mRNA expression levels of ABCA1 and ABCG1 were recorded to assess the possible contributions of the two efflux pathways. Because a previous study (23) reported a proinflammatory state in monocytes and monocyte-derived macrophages from low HDL-C subjects, we also measured mRNA expression of selected inflammatory genes in monocytes isolated from the study subjects.…”

Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies

“…In addition, glycosylation of apoA1, which primarily acts via ABCA1, has been shown to suppress its ability to remove cholesterol from cells (74). HDL also has anti-inflammatory and anti-oxidant properties in cells of the vessel wall (75; 76) Monocyte-derived macrophages isolated from subjects with low HDL cholesterol manifest a pro-inflammatory phenotype (77).…”

Vascular Inflammation in Patients With Impaired Glucose Tolerance and Type 2 Diabetes

“…34 Moreover, monocyte-derived macrophages isolated from individuals with low HDL cholesterol concentrations manifest a proinflammatory phenotype. 35 Therefore, mean and maximum TBR may be associated with low HDL cholesterol and increased small, dense LDL particles rather than circulating LDL cholesterol level. The results of this study also showed that hyperglycemia-related variables, such as the fasting plasma glucose and HbA 1c , were significantly associated with the vascular inflammation measured by FDG-PET.…”