Copyright © 2003 by the European Society of Cardiology.
Clinical research
Patients with familial hypercholesterolaemia show enhanced spontaneous chemokine release from peripheral blood mononuclear cells ex vivo
Dependency of xanthomas/xanthelasms, smoking and gender
a Lipid Clinic, Rikshospitalet University Hospital, Oslo, Norway
b Research Institute for Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
c MSD Cardiovascular Research Center, Rikshospitalet University Hospital, Oslo, Norway
d Section of Clinical Immunology and Infection Diseases, Medical Department, Rikshospitalet University Hospital, Oslo, Norway
e Institute for Clinical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway
* Correspondence to: Marit S. Nenseter, Senior Research Scientist, Research Institute for Internal Medicine, Rikshospitalet University Hospital, 0027 Oslo, Norway. Tel: +47-23073621; Fax: +47-23073630
E-mail address: maritn{at}klinmed.uio.no
Received 12 March 2003; revised 27 June 2003; accepted 31 July 2003
Abstract
Aims Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among patients with heterozygous FH, and we hypothesized that inflammatory mediators such as chemokines could contribute to atherogenesis in these patients.
Methods and results We compared peripheral blood mononuclear cells (PBMCs) from FH patients with an identical mutation with PBMCs from sex- and age-matched healthy controls with respect to spontaneous and oxidized low density lipoprotein (oxLDL)-stimulated release of chemokines. Our main findings were: (1) PBMCs from FH patients spontaneously released significantly higher levels of macrophage inflammatory protein (MIP)-1
, MIP-1ß and interleukin (IL)-8, and had a significantly lower oxLDL-stimulatory ratio for MIP-1 and MIP-1ß than cells from healthy controls. (2) Spontaneous release of these chemokines correlated positively and stimulatory ratio correlated negatively with plasma concentrations of total and LDL cholesterol. (3) Among FH patients, release of MIP-1, MIP-1ß and IL-8 from PBMCs varied with the presence of xanthomas/xanthelasms, smoking and gender. (4) In vitro studies showed that FH serum but not control serum was able to induce enhanced spontaneous release of chemokines in PBMCs from both FH patients and control subjects.
Conclusions Our data may suggest that a pathophysiological consequence of FH is enhanced chemokine responses, which in turn may promote recruitment and activation of leukocytes within the vessel wall, contributing to atherosclerosis as well as to the different phenotypes in these patients with an identical FH mutation.
Key Words: Familial hypercholesterolaemia • Premature coronary artery disease • Xanthomas/xanthelasms • Chemokines
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