Patients with familial hypercholesterolaemia show enhanced spontaneous chemokine release from peripheral blood mononuclear cells ex vivo. Dependency of xanthomas/xanthelasms, smoking and gender.
OBJECTIVE
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.


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)-1alpha, MIP-1beta and interleukin (IL)-8, and had a significantly lower oxLDL-stimulatory ratio for MIP-1alpha and MIP-1beta 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-1alpha, MIP-1beta 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.
Holven
Kirsten B
KB
Lipid Clinic, Rikshospitalet University Hospital, Oslo, Norway.
Myhre
Anne M
AM
Aukrust
Pål
P
Hagve
Tor Arne
TA
Ose
Leiv
L
Nenseter
Marit S
MS
D000328:Adult; D000368:Aged; D018925:Chemokines / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism*; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D014973:Xanthomatosis / Q000150:complications
D018925:Chemokines; D008078:Cholesterol, LDL; D008055:Lipids