HDL₃-Mediated Inhibition of Thrombin-Induced Platelet Aggregation and Fibrinogen Binding Occurs via Decreased Production of Phosphoinositide-Derived Second Messengers 1,2-Diacylglycerol and Inositol 1,4,5-tris-Phosphate

From the Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität, Münster (J.-R.N., M.W., G.A.); the Institut für Arterioskleroseforschung an der Universität Münster (M.W., U.S., G.A.); Experimentelle Hämostaseforschung, Medizinische Klinik und Poliklinik, Innere Medizin A, Münster (B.K., S.W.); and Universitätklinik Marienhospital, Ruhr-Universität Bochum, Herne (M.T.), Germany.

Correspondence to Michael Walter, MD, Institut für Klinische Chemie und Laboratoriumsmedizin, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany.

Abstract—We demonstrate that physiological concentrations of HDL₃ inhibit the thrombin-induced platelet fibrinogen binding and aggregation in a time- and concentration-dependent fashion. The underlying mechanism includes HDL₃-mediated inhibition of phosphatidylinositol 4,5-bis-phosphate turnover, 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate formation, and intracellular calcium mobilization. The inhibitory effects of HDL₃ on inositol 1,4,5-tris-phosphate formation and intracellular calcium mobilization were abolished after covalent modification of HDL₃ with dimethylsuberimidate. Furthermore, they could be blocked by calphostin C and bis-indolylmaleimide, 2 highly selective and structurally unrelated protein kinase C inhibitors. However, the inhibitory effects of HDL₃ were not blocked by H89, a protein kinase A inhibitor. In addition, HDL₃ failed to induce cAMP formation but stimulated the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. We observed a close temporal relationship between the HDL₃-mediated inhibition of thrombin-induced inositol 1,4,5-tris-phosphate formation, intracellular calcium mobilization, and fibrinogen binding and the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. Taken together, these findings indicate that the HDL₃-mediated inhibition of thrombin-induced fibrinogen binding and aggregation occurs via inhibition of phosphatidylinositol 4,5-bis-phosphate turnover and formation of 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Protein kinase C may be involved in this process.

Key Words: high-density lipoprotein • protein kinase C • signal transduction • platelet aggregation • fibrinogen

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