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 hyperchole sterolemia. However, the underlying mechanism of this putatively ather ogenic effect is unknown. Because intracellular pH (pH(i)) may play an important role in platelet function, we examined the influence of LDL on pH(i) and Na+/H+ antiport activity in human platelets and compared it with the effect of [3-methylsulfonyl-4-piperidinobenzoyl] guanidin e hydrochloride (HOE 694), a selective Na+/H+ antiport inhibitor. Meth ods and Results Using a fluorescent dye technique, we demonstrated tha t incubation of platelets with physiological concentrations of LDL or with HOE 694 decreased pH(i). In addition, both LDL and HOE 694 inhibi ted the Na+/H+ antiport in platelets treated with sodium propionate or thrombin. The inhibitory effect of LDL was observed both in normal an d in glycoprotein (GP)IIb/IIIa- as well as in GPIIIb (CD36)-deficient platelets and was not influenced by the covalent modification of apoli poprotein B lysine residues, suggesting that specific LDL binding site s were not involved. Thrombin-induced phosphoinositide breakdown, diac ylglycerol formation, and Ca2+ mobilization. as well as platelet aggre gation and granule secretion, were potentiated by both LDL and HOE 694 . pH(i) and Na+/H+ antiport activity were significantly reduced in pla telets from patients with familial hypercholesterolemia. Both paramete rs were normalized after normalization of LDL levels by apheresis trea tment. Conclusions LDL inhibits the Na+/H+ antiport most likely via re ceptor-independent mechanisms, thereby augmenting platelet reactivity. This novel mechanism explains increased platelet reactivity in patien ts with familial hypercholesterolemia and may contribute to the athero genic potential of LDL.