title: Coupling factor 6 enhances the spontaneous microaggregation of platelets by decreasing cytosolic cAMP irrespective of antiplatelet therapy.
abstract: The spontaneous microaggregation of platelets (SMAPs) is a marker for the prognosis of patients with cardiovascular diseases. Coupling factor 6 (CF6) binds to the plasma membrane ATP synthase and functions as a pro-atherogenic molecule in the cardiovascular system. However, the role of CF6 in SMAPs and stroke remains unknown. In 650 consecutive patients, including those with acute-onset stroke, and 20 control subjects, platelet-rich plasma (PRP) was obtained, and SMAP was measured using a laser light-scattering aggregometer. The cytosolic cyclic adenosine monophosphate (cAMP) concentration in platelets was measured using an enzyme-linked immunosorbent assay. CF6 increased SMAPs in patients and control subjects to a similar degree by binding to the α- and β-subunits of ATP synthase and inducing intracellular acidosis. It was abolished by PRP pretreatment with antibodies against CF6, and the α- or β-subunit of the plasma membrane ATP synthase, and the ATP synthase inhibitor efrapeptin. CF6 increased SMAPs in patient groups with and without antiplatelet therapy to a similar degree, and no difference was found among the subgroups taking aspirin, thienopyridine or cilostazol. The cytosolic cAMP concentration in platelets was decreased by CF6 in the presence of the direct adenylate cyclase activator forskolin. Pretreatment of PRP with the Gs activator cholera toxin blocked the decrease, whereas the Gi inactivator pertussis toxin and cilostazol had no influence. The CF6-induced acceleration of SMAPs was suppressed by cholera toxin but not by cilostazol or pertussis toxin. CF6 enhanced SMAPs by decreasing cytosolic cAMP. Because it was observed irrespective of antiplatelet agents, CF6 appears to be a novel target for antiplatelet therapy.
authors: Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors: Takanori
authors: T
authors: Sukekawa
authors: Tomohiro
authors: T
authors: Osanai
authors: Fumie
authors: F
authors: Nishizaki
authors: Norifumi
authors: N
authors: Metoki
authors: Joji
authors: J
authors: Hagii
authors: Takaatsu
authors: T
authors: Kamada
authors: Minoru
authors: M
authors: Yasujima
authors: Hirofumi
authors: H
authors: Tomita
authors: Koji
authors: K
authors: Magota
authors: Ken
authors: K
authors: Okumura
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism; D000368:Aged; D019540:Area Under Curve; D015153:Blotting, Western; D002772:Cholera Toxin / Q000494:pharmacology; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D025261:Mitochondrial Proton-Translocating ATPases / Q000494:pharmacology*; D010086:Oxidative Phosphorylation Coupling Factors / Q000494:pharmacology*; D019007:P-Selectin / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011863:Radioimmunoassay; D012307:Risk Factors; D013268:Stimulation, Chemical; D020521:Stroke / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D010086:Oxidative Phosphorylation Coupling Factors; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D025181:ATP Synthetase Complexes; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases; D000077407:Cilostazol