Tendon xanthomas in familial hypercholesterolemia are associated with a differential inflammatory response of macrophages to oxidized LDL

Abstract

Tendon xanthomas (TX) are pathognomonic lipid deposits commonly found in familial hypercholesterolemia (FH) patients. The aim of this study was to determine whether macrophages from FH patients with TX (TX+) have higher predisposition to foam cells formation after oxidized LDL (oxLDL) overload than those from FH patients without TX (TXÀ), and if their differential gene expression profile could explain these different phenotypes. Total RNA pools from macrophages from FH patients TX+ and TXÀ were analyzed using Affymetrix oligonucleotide arrays to evaluate the gene expression profile in presence and absence of oxLDL. Also, the intracellular lipid content was measured by fluorescence flow cytometry. Results of these studies suggest that macrophages from FH subjects TX+ compared to those TXÀ have a differential response to oxLDL, since they show higher intracellular cholesterol ester accumulation and a differential gene expression profile. The gene array data were validated by relative quantitative real-time RT-PCR and quantitative ELISA in culture media and plasma samples. FH subjects TX+ showed increased plasma tryptase, TNF-a, IL-8 and IL-6 concentrations. We propose that TX formation are associated with higher intracellular lipid content, and higher inflammatory response of macrophages in response to oxLDL.

Achilles Tendon Ultrasonography for Diagnosis of Familial Hypercholesterolemia Among Japanese Subjects

“…17 Furthermore, Artieda et al reported that AT xanthoma formation was associated with higher intracellular lipid content, and a stronger inflammatory response of macrophages to oxidized LDL. 18 Accordingly, we speculate that the oxidative and inflammatory properties of LDL might play significant roles in the formation of AT xanthomas.…”

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia

“…Oosterveer et al 24 reported that the presence of tendon xanthomas in patients with FH is associated with genetic variation in the randomized controlled trials and LDL oxidation pathways. Moreover, Artieda et al 29 reported that tendon xanthoma formation might be associated with higher intracellular lipid content, and a stronger inflammatory response of macrophages to oxidized LDL. Accordingly, we speculate that, in addition to cholesterol efflux capacity, the antioxidative and anti-inflammatory properties of HDL might play a significant role in the formation of corneal arcus and Achilles tendon xanthomas.…”

Xanthomas: Clinical and pathophysiological relations

“…Genetic predisposition of macrophages to high inflammatory responses consequently takes part in the pathogenesis of xanthomas. Free tryptase (released from mast cells, possessing 44% homology with the serine protease) can degrade HDL 3 particles and decrease the efficiency of reverse cholesterol transport 20 .…”