Platelet function in patients with familial hypertriglyceridemia: evidence that platelet reactivity is modulated by apolipoprotein E content of very-low-density lipoprotein particles.
We evaluated platelet function in patients with familial hypertriglyceridemia (FHTG). Compared with healthy gender-matched controls, platelets from patients showed lower aggregation (P < .01) and thromboxane formation (P < .01) in response to collagen. Very-low-density lipoprotein (VLDL) particles obtained from the patients inhibited collagen-induced aggregation, whereas VLDL particles from controls had opposite effects. The VLDL-induced effect was regulated by its apolipoprotein E (apoE) content. Indeed, apoE-VLDL-rich fractions caused antiaggregative effects, whereas apoE-VLDL-poor fractions produced a strong proaggregative response. Since we have recently demonstrated that VLDL particles may regulate the activity of platelet low-density lipoprotein (LDL) receptor by a phenomenon of downregulation and desensitization, in this study, we have investigated the effect of prolonged exposure to circulating VLDL levels on the activity of platelet LDL receptor by a double-blind controlled study with gemfibrozil (600 mg twice daily) in 18 subjects with FHTG. Platelets from patients exhibited fewer platelet LDL receptors and 125I-LDL binding was saturable at a lower protein concentration. After 6 months, gemfibrozil therapy versus placebo had a marked lipid-lowering effect, significantly decreased triglycerides (61%), VLDL cholesterol (72%), apoB (28%), and apoE (55%), and increased high-density lipoprotein (44%) and apoA-I (18%). Furthermore, gemfibrozil affected the apoprotein composition of VLDL: total protein increased by 28%, the molar ratio of apoE to apoB decreased 64%, and apoE content decreased 55%. However, no differences in phospholipid, triglyceride, or total cholesterol were detected. Moreover, platelet function was markedly altered by gemfibrozil therapy. Collagen-induced aggregation and thromboxane formation were significantly enhanced (P < .01). The initial antiaggregative pattern of VLDL particles was changed to a significant proaggregative effect (P < .01), and the number of LDL binding sites was markedly upregulated (P < .001). Both receptor upregulation and the change in the aggregative effect of VLDL particles were associated with the reduction of apoE content in VLDL particles (P < .05). The overall results indicate that in the regulation of platelet reactivity in hypertriglyceridemic patients, apoE content of VLDL particles and their interaction with the platelet LDL receptor are involved.
Universidad Rovira i Virgili, Facultad de Medicina, Unitat de Recerca en Lípids i Arteriosclerosi, Reus, Spain.
J
J
Pedreño
E
E
Hurt-Camejo
O
O
Wiklund
L
L
Badimón
L
L
Masana
D000328:Adult; D001057:Apolipoproteins E / Q000032:analysis*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D004311:Double-Blind Method; D015248:Gemfibrozil / Q000494:pharmacology; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D011973:Receptors, LDL / Q000032:analysis
D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D015248:Gemfibrozil