(Circulation. 1997;95:1370-1377.)
© 1997 American Heart Association, Inc.
Articles |
Low-Density Lipoproteins Inhibit the Na+/H+ Antiport in Human Platelets
A Novel Mechanism Enhancing Platelet Activity in Hypercholesterolemia
Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität, Münster, Germany (J.-R.N., M.W., G.A.); Medizinische Klinik I, Universitätsklinik Marienhospital, Ruhr-Universität-Bochum, Herne, Germany (M.T., W.Z.); Experimentelle Hämostaseforschung, Medizinische Klinik und Poliklinik, Innere Medizin A, Münster, Germany (B.K., S.W.); and Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany (M.W., U.S., G.A.).
Correspondence to Prof Walter Zidek, MD, Medizinische Klinik I, Universitätsklinik Marienhospital, Ruhr-Universität-Bochum, Hölkeskampring 40, D-44625 Herne, FRG.
Background LDL have been reported to augment platelet activation, and increased platelet reactivity has been observed in familial hypercholesterolemia. However, the underlying mechanism 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.
Methods and 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 mechanism explains increased platelet reactivity in patients with familial hypercholesterolemia and may contribute to the atherogenic potential of LDL.
Key Words: platelets • lipoproteins • hypercholesterolemia
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