title: Factor Xa Inhibitor Suppresses the Release of Phosphorylated HSP27 from Collagen-Stimulated Human Platelets: Inhibition of HSP27 Phosphorylation via p44/p42 MAP Kinase.
abstract: Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase.
authors: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.|Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Masanori
authors: M
authors: Tsujimoto
authors: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.|Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Gen
authors: G
authors: Kuroyanagi
authors: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Rie
authors: R
authors: Matsushima-Nishiwaki
authors: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Yuko
authors: Y
authors: Kito
authors: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Yukiko
authors: Y
authors: Enomoto
authors: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Hiroki
authors: H
authors: Iida
authors: Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Shinji
authors: S
authors: Ogura
authors: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Takanobu
authors: T
authors: Otsuka
authors: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.|Department of Clinical Laboratory, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Haruhiko
authors: H
authors: Tokuda
authors: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Osamu
authors: O
authors: Kozawa
authors: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Toru
authors: T
authors: Iwama
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000737:chemistry*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use; D000069552:Rivaroxaban / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D020246:Venous Thrombosis
chemical_list: D065427:Factor Xa Inhibitors; D055551:HSP27 Heat-Shock Proteins; D011725:Pyridines; D013844:Thiazoles; D003094:Collagen; D000069552:Rivaroxaban; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C552171:edoxaban