Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets. A novel mechanism enhancing platelet activity in hypercholesterolemia.
BACKGROUND
LDL have been reported to augment platelet activation, and increased platelet reactivity has been observed in familial hypercholesterolemia. However, the underlying mechanisms of this putatively atherogenic effect is unknown. Because intracellular pH (pHi) may play an important role in platelet function, we examined the influence of LDL on pHi and Na+/H+ antiport activity in human platelets and compared it with the effect of [3-methylsulfonyl-4-piperidinobenzoyl] guanidine hydrochloride (HOE 694), a selective Na+/H+ antiport inhibitor.


RESULTS
Using a fluorescent dye technique, we demonstrated that incubation of platelets with physiological concentrations of LDL or with HOE 694 decreased pHi. In addition, both LDL and HOE 694 inhibited the Na+/H+ antiport in platelets treated with sodium propionate or thrombin. The inhibitory effect of LDL was observed both in normal and in glycoprotein (GP)IIb/IIIa-as well as in GPIIIb (CD36)-deficient platelets and was not influenced by the covalent modification of apolipoprotein B lysine residues, suggesting that specific LDL binding sites were not involved. Thrombin-induced phosphoinositide breakdown, diacylglycerol formation, and Ca2+ mobilization, as well as platelet aggregation and granule secretion, were potentiated by both LDL and HOE 694. pHi and Na+/H+ antiport activity were significantly reduced in platelets from patients with familial hypercholesterolemia. Both parameters were normalized after normalization of LDL levels by apheresis treatment.


CONCLUSIONS
LDL inhibits the Na+/H+ antiport most likely via receptor-independent mechanisms, thereby augmenting platelet reactivity. This novel mechanisms explains increased platelet reactivity in patients with familial hypercholesterolemia and may contribute to the atherogenic potential of LDL.
Nofer
J R
JR
Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster, Germany.
Tepel
M
M
Kehrel
B
B
Wierwille
S
S
Walter
M
M
Seedorf
U
U
Zidek
W
W
Assmann
G
G
D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006938:Hyperlipoproteinemia Type II / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D019007:P-Selectin / Q000097:blood; D010716:Phosphatidylinositols / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D060149:Tetraspanin 30; D013917:Thrombin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D015703:Antigens, CD; C554586:CD63 protein, human; D006146:Guanidines; D008077:Lipoproteins, LDL; D019007:P-Selectin; D010716:Phosphatidylinositols; D010980:Platelet Membrane Glycoproteins; D011422:Propionates; D011453:Prostaglandins; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D060149:Tetraspanin 30; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; C514135:sodium propionate; D010738:Type C Phospholipases; D013917:Thrombin; C029658:propionic acid