Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.
Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
A Phillip
AP
Owens
Freda H
FH
Passam
Silvio
S
Antoniak
Stephanie M
SM
Marshall
Allison L
AL
McDaniel
Lawrence
L
Rudel
Julie C
JC
Williams
Brian K
BK
Hubbard
Julie-Ann
JA
Dutton
Jianguo
J
Wang
Peter S
PS
Tobias
Linda K
LK
Curtiss
Alan
A
Daugherty
Daniel
D
Kirchhofer
James P
JP
Luyendyk
Patrick M
PM
Moriarty
Shanmugam
S
Nagarajan
Barbara C
BC
Furie
Bruce
B
Furie
Douglas G
DG
Johns
Ryan E
RE
Temel
Nigel
N
Mackman
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism
D000924:Anticholesteremic Agents; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C495345:TLR4 protein, human; C495368:TLR6 protein, human; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; D019821:Simvastatin