Abstract
ObjectiveAnimal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate the hypothesis that elevated oxLDL-C induce proinflammatory monocytes and increased release of monocyte-derived microparticles (MMPs), as well as up-regulation of CD36, chemokine receptors and proinflammatory factors through CD36-dependent pathways and that this is associated with accelerated atherosclerosis in subjects with heterozygous familial hypercholesterolemia (FH), in particular in the presence of Achilles tendon xanthomas (ATX).Approach and ResultsWe studied thirty FH subjects with and without ATX and twenty-three healthy control subjects. Intima-media thickness (IMT) and Achilles tendon (AT) thickness were measured by ultrasonography. Monocyte classification and MMP analysis were performed by flow cytometry. Monocyte expression of genes involved in atherosclerosis was determined by quantitative PCR. IMT and oxLDL-C were increased in FH subjects, especially in the presence of ATX. In addition, FH subjects had elevated proportions of intermediate CD14++CD16+ monocytes and higher circulating MMP levels. Stepwise linear regression identified oxLDL-C, gender and intermediate monocytes as predictors of MMPs. Monocyte expression of pro-atherogenic and pro-inflammatory genes regulated by oxLDL-C-CD36 interaction was increased in FH, especially in ATX+ subjects. Monocyte chemokine receptor CX3CR1 was identified as an independent contributor to IMT.ConclusionsOur data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in FH, particularly in the presence of ATX, by inducing pro-inflammatory monocytes and increased release of MMPs along with elevated monocyte expression of oxLDL-C-induced atherosclerosis-related genes.
Highlights
The attachment and subsequent transmigration of circulating monocytes into the subendothelial space is facilitated by hypercholesterolemia-induced expression of adhesion molecules on endothelial cells and their secretion of chemoattractant factors
Our data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in familial hypercholesterolemia (FH), in the presence of Achilles tendon xanthomas (ATX), by inducing pro-inflammatory monocytes and increased release of monocyte-derived microparticles (MMPs) along with elevated monocyte expression of oxLDLC-induced atherosclerosis-related genes
Routine laboratory measurements were all within age- and gender-specific reference intervals and no significant differences were observed between groups except for increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and oxidized LDL cholesterol (oxLDL-C) in FH compared to control subjects as well as in FH ATX+ compared to FH ATX- subjects
Summary
The attachment and subsequent transmigration of circulating monocytes into the subendothelial space is facilitated by hypercholesterolemia-induced expression of adhesion molecules on endothelial cells and their secretion of chemoattractant factors. The monocytes differentiate into macrophages, which internalize lipoproteins and become proinflammatory resulting in further recruitment of monocytes and promoting inflammation and progression of atherosclerosis as reviewed in [1]. Uptake of oxidized LDL cholesterol (oxLDL-C) by the scavenger receptor CD36 in monocytes and macrophages leads to an up-regulation of CD36 expression through activation of the transcription factor PPAR-γ, thereby creating a ‘vicious’ feed-forward cycle of increasing oxLDL-C uptake, converting the monocyte/macrophage into an atherogenic foam cell as reviewed in [6]. Other effects of oxLDL-C binding to CD36 include activation of the transcription factor NFκB which induces production of proinflammatory cytokines and a proinflammatory phenotype [7]
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