Differential effects of ganodermic acid S on the thromboxane A2-signaling pathways in human platelets

Ganodermic acid S (GAS) [lanosta-7,9(11),24-triene-3 beta,15 alpha-diacetoxy-26-oic acid], isolated from the Chinese medicinal fungus Ganoderma lucidum (Fr.) Karst (Polyporaceae), exerted a concentration-dependent inhibition on the response of human gel filtered platelets (GFP) to U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxyprostaglandin F-2 alpha), a thromboxane (TX) A(2) mimetic. GAS at 2 mu M inhibited 50% of cell aggregation. GAS at 7.5 mu M inhibited 80% of Ca2+ mobilization, 40% of phosphorylation of myosin light chain and pleckstrin, 80% of cw-granule secretion, and over 95% of aggregation. GAS also strongly inhibited U46619 induced diacylglycerol formation, arachidonic acid release, and TXB2 formation. An immunoblotting study of protein-tyrosine phosphorylation showed that GAS inhibited the formation of phosphotyrosine proteins at the steps involving the engagement of integrin alpha(IIb)beta(3) and aggregation. However, GAS did not inhibit U46619-induced platelet shape change or the inhibitory effect of U46619 on the prostaglandin El evoked cyclic AMP level in GFP. It is concluded that GAS inhibits platelet response to TXA(2) on the receptor-G(q)-phospholipase C beta 1 pathway, but not on the receptor-G, pathway. (C) 1999 Elsevier Science Inc.